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‘Dramatic’ inroads against aggressive brain cancer

Cutting-edge therapy shrinks tumors in early glioblastoma trial

Haley Bridger

Mass General Communications

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.

In a paper published Wednesday in The New England Journal of Medicine, researchers from Mass General Cancer Center shared the results for the first three patient cases from a Phase 1 clinical trial evaluating a new approach to CAR-T therapy for glioblastoma.

Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.

Left: MRI in Participant 3 before infusion. Right: After infusion on day five.

Image courtesy of The New England Journal of Medicine

“This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need,” said co-author Bryan Choi , a neurosurgeon at Harvard-affiliated Mass General and an assistant professor at Harvard Medical School. “The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way.”

The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus , director of the Cellular Immunotherapy Program and an associate professor at the Medical School. Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next-generation genetically modified T cells from the bench to clinical trials in patients with cancer.

“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus. “These results are exciting, but they are also just the beginning — they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”

CAR-T (chimeric antigen receptor T-cell) therapy works by using a patient’s own cells to fight cancer — it is known as the most personalized way to treat the disease. A patient’s cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly. Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.

CAR-T therapies have been approved for the treatment of blood cancers, but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some malignant cells to continue to evade the immune system’s detection even after treatment with CAR-T. Maus’ team is working to overcome this challenge by combining two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules. The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.

In the new study, the three patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study. All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence.

A 74-year-old man had his tumor regress rapidly but transiently after a single infusion of the new CAR-TEAM cells.
A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving the cells, an MRI showed a decrease in the tumor’s size by 18 percent. By day 69, the tumor had decreased by 60 percent, and the response was sustained for more than six months.
A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after the infusion showed near-complete tumor regression.

The authors note that despite the remarkable responses among the first three patients, they observed eventual tumor progression in all the cases, though in one case, there was no progression for over six months. Progression corresponded in part with the limited persistence of the CAR-TEAM cells over the weeks following infusion. As a next step, the team is considering serial infusions or preconditioning with chemotherapy to prolong the response.

“We report a dramatic and rapid response in these three patients. Our work to date shows signs that we are making progress, but there is more to do,” said co-author Elizabeth Gerstner, a Mass General neuro-oncologist.

In addition to Choi, Maus, and Gerstner, other authors are Matthew J. Frigault, Mark B. Leick. Christopher W. Mount, Leonora Balaj, Sarah Nikiforow, Bob S. Carter, William T. Curry, and Kathleen Gallagher.

The study was supported in part by the National Gene Vector Biorepository at Indiana University, which is funded under a National Cancer Institute contract.

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Researchers reveal promising treatment target for resistant brain cancer

Fralin Biomedical Research Institute scientists identify key cell pathway in glioblastoma, potentially opening new avenues for therapy.

John Pastor

17 May 2024

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For many patients with a deadly type of brain cancer called glioblastoma, chemotherapy resistance is a big problem. But now, Virginia Tech researchers led by Zhi Sheng (center) of the Fralin Biomedical Research Institute at VTC may have moved a step closer to a solution.

For many patients with a deadly type of brain cancer called glioblastoma, chemotherapy resistance is a big problem.

Current standard treatments, including surgery, radiation, and chemotherapy using the drug temozolomide, have limited effectiveness and have not significantly changed in the past five decades. Although temozolomide can initially slow tumor progression in some patients, typically the tumor cells rapidly become resistant to the drug.

But now, Virginia Tech researchers with the Fralin Biomedical Research Institute at VTC may have moved a step closer to a solution.

Working with glioblastoma cell cultures, including glioblastoma stem cells derived from patient specimens, and laboratory mouse models harboring human cancer cells, scientists have pinpointed an effective molecular signaling pathway that is thought to be crucial for cancer cell survival during temozolomide treatment. The findings are now online in iScience , an open-access journal of Cell Publishing.

“In the past 50 years, treatment options for glioblastoma have remained largely unchanged, relying on surgery, radiation, and temozolomide,” said Zhi Sheng, senior author of the study and assistant professor at the Fralin Biomedical Research Institute. “However, temozolomide's effectiveness is limited, and resistance to the chemotherapy inevitably develops in patients. Since it's the only currently available approved chemotherapy that can effectively reach the brain, finding ways to restore its effectiveness is crucial in addressing the treatment failure in glioblastoma.”

Researchers examined the Phosphoinositide 3 Kinase (PI3K) molecular signaling pathway, which is like a communication system inside cells. It tells cells how to grow, survive, and divide. When this pathway is activated, it can promote cancer growth, so scientists and clinicians generally thought blocking it could be a way to treat cancer.

Their results have not been successful.

In the new research, Fralin Biomedical Research Institute scientists found that in some brain cancer patients who didn’t respond to treatment, levels were high of a specific form of the signaling protein called PI3K-beta that helps regulate cellular processes.

When they blocked just PI3K-beta in cell cultures and mouse models harboring cancer cells, the tumor cells became more sensitive to temozolomide treatment. In addition, using a drug that blocks PI3K-beta along with the usual treatment slowed down the cancer cells' growth.

Researchers are uncertain why PI3K, in its various forms, are very similar in structure yet do different things in the body.

“The reason previous treatments targeting the PI3K pathway failed is because they didn't distinguish between PI3K-beta and its related proteins,” Sheng said. “This research shows that PI3K-beta is specific to glioblastoma, making it the crucial target for effective treatment.”

Going forward, overcoming the blood-brain barrier remains a hurdle for delivering P13K-beta inhibitors into the brain, which will be crucial for translating the findings into the clinic to help patients.

“We will resolve these issues in our future studies,” Sheng said.

Co-first authors of the study are Kevin Pridham, a former postdoctoral associate at the Fralin Biomedical Research Institute, and Kasen Hutchings and Patrick Beck, two former medical students at the Virginia Tech Carilion School of Medicine who are pursuing their medical careers in radiology in Las Vegas and pediatrics in Philadelphia, respectively.

Cell specimens were provided by Carilion Clinic. Study results are in part based on data generated by The Cancer Genome Atlas Research Network, the Dependency Map, the Genotype-Tissue Expression, or the Chinese Glioma Genome Atlas. The research was supported by the National Institutes of Health.

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Preliminary Clinical Trial Results Show ‘Dramatic and Rapid’ Regression of Glioblastoma after Next Generation CAR-T Therapy

Members of the Mass General Cancer Center INCIPIENT team (from left to right): Elizabeth Gerstner, MD, William Curry, MD, Marcela Maus, MD, PhD, Bryan Choi, MD, PhD, Kathleen Gallagher, PhD and Matthew Frigault, MD.

Mass General Cancer Center researchers took a new approach to CAR-T, engineering CAR-TEAM cells to treat mixed cell populations within tumors
Working in collaboration with Mass General neurosurgeons, the team tested the approach in a phase 1 clinical trial of patients with recurrent glioblastoma
First three patients in the trial showed dramatic responses within days

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment. In a paper published today in The New England Journal of Medicine , researchers from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, shared the results for the first three patient cases from a phase 1 clinical trial evaluating a new approach to CAR-T therapy for glioblastoma (GBM). The trial, known as INCIPIENT, is designed to evaluate the safety of CARv3-TEAM-E T cells in patients with recurrent GBM. Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.

Mass General Cancer Center INCIPIENT team

“This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need,” said Bryan Choi, MD, PhD , neurosurgeon and associate director of the Center for Brain Tumor Immunology and Immunotherapy, Cellular Immunotherapy Program, Mass General Cancer Center and Department of Neurosurgery. “The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way.”

The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus, MD, PhD , director of the Cellular Immunotherapy Program at the Mass General Cancer Center, Paula J. O'Keeffe chair in Oncology, and faculty of the Krantz Family Center for Cancer Research. Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next generation genetically modified T cells from the bench to clinical trials in patients with cancer.

“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus. “These results are exciting, but they are also just the beginning—they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”

Studies like this one show the promise of cell therapy for treating incurable conditions. Mass General Brigham’s Gene and Cell Therapy Institute, where Maus is Associate Head & Head of Cell Therapies , is helping to translate scientific discoveries made by researchers into first-in-human clinical trials and, ultimately, life-changing treatments for patients. The Institute’s multidisciplinary approach sets it apart from others in the space, helping researchers to rapidly advance new therapies and push the technological and clinical boundaries of this new frontier.

CAR-T therapy works by using a patient's own cells to fight cancer—it is known as the most personalized way to treat cancer. A patient's cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly. Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.

CAR-T therapies have been approved for the treatment of blood cancers but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some cancer cells to continue to evade the immune system’s detection, even after treatment with CAR-T. Maus’s team is working to overcome this challenge of tumor heterogeneity with an innovative strategy that combines two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules (TEAMs). The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.

Maus and colleagues previously developed CAR-T cells to target a common cancer mutation known as EGFRvIII, but when that alone had limited effects, her team engineered these CAR-T cells to deliver TEAMs against wild-type EGFR, which is not detected in normal brain tissue but is expressed in more than 80 percent of cases of GBM.

The combination approach showed promise in preclinical models of glioblastoma , encouraging the research team to pursue clinical translation. In collaboration with Mass General neurosurgeons and neuro-oncologists, including Elizabeth Gerstner, MD, and William Curry, MD, as well as specialists in cell therapy delivery, Matthew Frigault, MD, and immunotherapy monitoring, Kathleen Gallagher, PhD, the team launched INCIPIENT (ClinicalTrials.gov number, NCT05660369), a non-randomized, open label, single-site Phase 1 study.

Three patients were enrolled in the study between March 2023 and July 2023. Patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study.

All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence:

A 74-year-old man had his tumor regress rapidly, but transiently after a single infusion of the new CAR-TEAM cells. Blood and cerebrospinal fluid from the patient showed a decrease in EGFRvIII and EGFR copy numbers, eventually becoming undetectable.
A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving CAR-TEAM cells, an MRI showed a decrease in the tumor’s size by 18.5 percent. By day 69, the tumor had decreased by 60.7 percent, and the response was sustained for over 6 months.
A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after a single infusion of CAR-TEAM cells showed near-complete tumor regression.

The patients tolerated the infusions well, though nearly all had fevers and altered mental status soon after infusion, as was expected from an active CAR-T therapy administered into the fluid around the brain. All patients were observed in the hospital before discharge.

To learn more, visit mauslab.com .

If you are interested in learning more about the INCIPIENT clinical trial, please call 617-724-6226 or email [email protected] . A member of our clinical team will contact you within 48 business hours.

Authorship: In addition to Choi, Maus and Gerstner, other authors include Matthew J. Frigault (MGH), Mark B. Leick (MGH), Christopher W. Mount (MGH), Leonora Balaj (MGH), Sarah Nikiforow (DFHCC), Bob S. Carter (MGH), William T. Curry (MGH), Kathleen Gallagher (MGH).

Disclosures: Disclosure forms provided by the authors is available with the full text of this article at NEJM.org.

Funding: This study was supported by a grant to MVM from Gateway for Cancer Research, the Mass General Cancer Center, Mass General Brigham, and philanthropic gifts. Support was also provided by the National Gene Vector Biorepository at Indiana University which is funded under National Cancer Institute contract HSN261201500003I Task Order No. HHSN26100077.

Paper cited: Choi BD et al. “Rapid Regression of Recurrent Glioblastoma with CARv3-TEAM-E T Cells.” New England Journal of Medicine DOI: 10.1056/NEJMoa2314390

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org .

Video: New CAR-T Therapy Shows Promise for Glioblastoma

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.

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New CAR-T Therapy Shows Promise for Glioblastoma: Why Is This Study Important?

Learn more about the findings and importance of a study led by a research and clinical team from the Mass General Cancer Center who is developing new cell therapy for patients with recurrent glioblastoma.

If you are interested in learning more about the INCIPIENT clinical trial, please call or email us. A member of our clinical team will contact you within 48 business hours.

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Emerging therapies for glioblastoma: current state and future directions

1 Institute of Human Virology, Key Laboratory of Tropical Diseases Control Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

Zhenzhen Zhang

2 Key Laboratory of Brain, Cognition and Education Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China

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Not applicable.

Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor with an extremely poor prognosis. Given the poor survival with currently approved treatments for GBM, new therapeutic strategies are urgently needed. Advances in decades of investment in basic science of glioblastoma are rapidly translated into innovative clinical trials, utilizing improved genetic and epigenetic profiling of glioblastoma as well as the brain microenvironment and immune system interactions. Following these encouraging findings, immunotherapy including immune checkpoint blockade, chimeric antigen receptor T (CAR T) cell therapy, oncolytic virotherapy, and vaccine therapy have offered new hope for improving GBM outcomes; ongoing studies are using combinatorial therapies with the aim of minimizing adverse side-effects and augmenting antitumor immune responses. In addition, techniques to overcome the blood-brain barrier (BBB) for targeted delivery are being tested in clinical trials in patients with recurrent GBM. Here, we set forth the rationales for these promising therapies in treating GBM, review the potential novel agents, the current status of preclinical and clinical trials, and discuss the challenges and future perspectives in glioblastoma immuno-oncology.

Gliomas account for almost 30% of primary brain tumors and 80% of all malignant ones. Based on their histopathological features, gliomas are traditionally classified by the World Health Organization (WHO) as grade I and II (low-grade gliomas), grade III (anaplastic) and IV (glioblastoma) [ 1 ], which indicate different degrees of malignancy. In recent years, with the development of genomic, transcriptomic and epigenetic profiling, substantial advances have been achieved in new concepts of classifying and treating gliomas [ 2 – 6 ] (Fig. 1 ), which will complement the morphology-alone-based classification. The classification of molecular subtypes within the glioma facilitates molecular diagnosis in a timely manner to offer opportunities to select the proper treatment modality according to the demand of clinical practice [ 7 ]. Glioblastoma (GBM) is the most common and aggressive type of primary brain tumors, which comprises up to 50% of all gliomas. Despite progress made in the current standard of care including surgery, radiotherapy, and pharmacotherapy (typically chemotherapy with concomitant temozolomide (TMZ)), the outcome for patients remains almost universally lethal [ 2 ], with a median overall survival (OS) ranging from 14.6 to 20.5 months [ 8 – 12 ]. The prognosis is much worse in elderly patients, who have an average survival from diagnosis of less than 8.5 months [ 13 ]. Given the poor survival with currently approved treatments for GBM, new therapeutic strategies are urgently needed.

An external file that holds a picture, illustration, etc.
Object name is 13046_2022_2349_Fig1_HTML.jpg

Genetic and epigenetic alterations in the genesis of gliomas. Shown are the relationships between the molecular lesions and pathobiology in the different types of gliomas. IDH , socitrate dehydrogenase; RELA , transcription factor p65; CDKN , cyclin-dependent kinase inhibitor; YAP1 , YES-associated protein 1; PF, posterior fossa; NF2 , neurofibromin 2; SEGA, subependymal giant cell astrocytoma; TSC , tuberous sclerosis; RTK, receptor tyrosine kinase; PDGFRA , platelet-derived growth factor receptor-α; TERT , telomerase reverse transcriptase; PTEN , phosphatase and tensin homologue; EGFR , epidermal growth factor receptor; H3F3A , histone H3.3; HIST1H3B , histone H3.1; ACVR1 , activin A receptor 1; ATRX , α-thalassemia/mental retardation syndrome X-linked; TP53 , tumour protein p53; PPM1D , protein phosphatase 1D; MGMT , O-6-methylguanine-DNA methyltransferase; g-CIMP, glioma CpG island methylator phenotype; Chr., chromosome; CIC , Drosophila homologue of capicua; Those IDH -mutant glioblastomas derived by progression from pre-existing lower grade astrocytomas (blue arrow) are tend to manifest in younger patients (≤50 years of age) compared with IDH wild-type tumors

For most patients with GBM, there is no known causative factors for this disease. The only well-established exogenous environmental cause of glioma is exposure to high doses of ionizing radiation [ 14 , 15 ]. Other risks including viral triggers (human cytomegalovirus) [ 16 ], obesity during adolescence [ 17 ], and family history of cancer [ 18 ] are continuing to be explored. Recent research has focused on identifying germline polymorphisms associated with risk of glioma, and reveals that genetic factors determine the degree of risk from these exposures [ 15 ]. Despite much efforts, little progress has been made in the survival outcomes of patients with GBM. The treatments fail mainly due to the unique molecular characteristics of GBM. Especially, the presence of a population of stem-like cells called glioma stem cells (GSCs) with ability of self-renewal and tumorigenicity, making it resistant to chemotherapy and radiotherapy [ 19 , 20 ]. GBM cells have the propensity to infiltrate/invade into the adjacent normal brain tissues of tumor and along blood vessels, which prevents complete resection of the tumor and limits the effect of local radiotherapy [ 21 ]. Other features of GBM contributing to poor prognosis include: 1) the existence of the blood-brain barrier (BBB), 2) the relative immune privileged status of the central nervous system (CNS). Thus, precise strategies based on tumor-intrinsic dominant signaling pathways and tumor-specific antigenic profiles may ultimately improve outcomes for GBM patients. Fortunately, advances in decades of investment in molecular pathogenesis of glioblastoma are rapidly translated into innovative clinical trials, utilizing improved genomic, epigenetic, transcriptomic and proteomic characterization of glioblastoma as well as the brain microenvironment and immune system interactions [ 22 ]. With these encouraging findings, immunotherapy including immune checkpoint blockade, chimeric antigen receptor T (CAR-T) cell therapy, oncolytic virotherapy and vaccine therapy have been actively tested in clinical trials for GBM [ 23 ]. Studies are ongoing to use combinatorial therapy with the aim of reducing adverse effects and enhancing antitumor responses [ 24 – 26 ]. Moreover, emerging insights into BBB features have yielded novel strategies to improve drug penetration into the tumor and infiltrative regions [ 27 ]. On the basis of preclinical work [ 28 – 33 ], focused ultrasound therapy have been tested in clinical trials and achieved improved treatment outcomes in patients with recurrent GBM [ 34 , 35 ], opening avenues for the development of innovative combinatorial strategies for targeting GBM. Herein, we set forth the rationales for these promising therapies in treating GBM, review the potential therapeutic targets, the current status of pre-clinical and clinical trials, and discuss the challenges and future directions of emerging therapies.

The CNS is an immunologically distinct site

Due to the presence of BBB, lack of dedicated lymphatic channels, low basal expression level of Major Histocompatibility Complex (MHC) class II molecules, paucity of antigen presenting cells (APC) and the constitutive expression of immunosuppressive cytokines such as TGF-ß, the CNS has long been considered as an immune-privileged site with restricted access that profoundly affects the capacity of T cells to exert their functions [ 36 ]. Consistent with this, high level of TGF-β was observed in intracranial gliomas in experimental models, leading to accumulation of both Tregs and immature dendritic cell (DC). This milieu prevented T-cell priming and re-stimulation, and ultimately impaired anti-tumor immune response [ 37 ]. However, more recent findings have improved our understanding of immunological mechanisms in the CNS. In 2015, Louveau et al. defined a classical lymphatic system in the CNS, which are able to carry both fluid and immune cells from the cerebrospinal fluid [ 38 ]. Thus, most antigen-presenting cells exiting the brain can travel to the deep cervical lymph nodes to prime T and B lymphocytes, indicating that immunogens present in the brain are capable of generating adequate immune responses [ 38 ]. Consistent with these findings, clinical data showed that downregulation of human leukocyte antigen (HLA) class I expression corresponds with poor prognosis in GBM [ 39 ] and low CD4 + T cell counts correlate with adverse outcomes in patients receiving conventional therapy for high-grade gliomas [ 40 ]. Regarding T lymphocytes, CD8 + T cells infiltrating in newly diagnosed glioblastoma was reported to prolong the survival of patients [ 41 ]. Taken together, these observations implicate that a T-cell response to GBM could potentially modulate outcome [ 36 ]. On the basis of evidence from preclinical and clinical studies, the CNS should more accurately be viewed as a unique immune environment. Immune reactions in the CNS are common, but take on a distinctive character, which is probably dictated by the natural microenvironment [ 42 ]. Normally, the CNS is immunologically quiescent in the healthy brain. In adults, microglia account for approximately 10% of CNS cells and maintain a quiescent phenotype in the normal CNS, expressing low levels of MHC molecules and costimulatory molecules [ 43 ]. Upon inflammatory conditions, peripheral leukocytes access the CNS and orchestrate immune responses, activated microglia upregulate MHC II molecules as well as costimulatory molecules and present antigens to activated lymphocytes [ 44 ], providing the fundamental basis for immunotherapy directed against brain tumors. Collectively, these findings support the notion that, while the brain is an immunologically specialized site, the immune microenvironment offers opportunities to develop immunotherapy for the treatment of GBM [ 45 ].

Current standard of care and immunotherapy

GBM is currently incurable because of its high recurrence after standard multimodality treatment, including surgery to remove the main tumor followed by concomitant radiation and adjuvant TMZ chemotherapy to target residual tumor cells. Because of the presence of GSCs, it requires complete destruction of the tumor, even a miniscule amount of residual tumor can lead to fatal recurrence [ 46 ]. Recently, intraoperative imaging techniques to maximize extent of resection have contributed considerably in defining the margins of glioblastoma [ 47 , 48 ]. However, radical extirpation of the tumor is not possible due to infiltration of the tumor into the surrounding brain, the role of image-guided surgery in maximizing extent of resection remains uncertain [ 46 ]. Currently, TMZ replaced nitrosoureas as the standard for patients with newly diagnosed GBM. To a certain extent, the success of this strategy depends on the methylation status of O-6 methylguanine-DNA methyl-guanine-methyltransferase ( MGMT ) [ 13 ]. In agreement to this, a Phase III trial demonstrated that GBM patients with MGMT promoter methylation achieved higher survival rates than patients with unmethylated MGMT promoter [ 49 ]. Subsequently, a randomized Phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT00006353","term_id":"NCT00006353"}} NCT00006353 ) in elderly GBM patients confirmed that patients with MGMT promoter methylation benefitted more from adjuvant TMZ with radiotherapy than radiotherapy alone [ 49 ], suggesting that the benefit seen in patients with MGMT promoter methylation may possibly correlated to addition of TMZ. Radiotherapy remains the primary treatment modality in unresectable GBM. Radiotherapy is usually combined with chemotherapy following surgery in different sequential combinations. According to a systematic review of randomized clinical trials, radiotherapy plus TMZ provides better survival outcomes than radiotherapy alone in treating GBM [ 50 ]. Recently, A multi-institutional GBM-molRPA cohort reported that conventionally fractionated standard radiotherapy significantly prolonged OS than short-course radiotherapy in selected elderly GBM patients treated with TMZ-based chemoradiation [ 51 ]. Given that TMZ can presents unwanted systemic toxicity, combination strategies with the aim of reducing adverse effects and augmenting anti-tumor responses are urgently needed. Recently, in an open-label, randomized, phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT01149109","term_id":"NCT01149109"}} NCT01149109 ), combined lomustine-TMZ chemotherapy prolonged overall OS survival compared with standard adjuvant therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter [ 52 ], providing new evidence that dual agent treatment may be superior to TMZ alone for GBM [ 53 ]. Despite multimodal therapies, the prognosis of GBM is still disappointing. To a certain degree, distinction of molecular subtypes within the glioma (Fig. (Fig.1) 1 ) offer possibilities to select the proper treatment modality according to the demand of clinical practice. However, to date, the classification scheme is of limited relevance for GBM treatment due to intratumoral heterogeneity.

Immunotherapy, which harnesses the body’s immune system to against cancer, has led to important clinical advances over the past few years [ 54 – 56 ]. On the basis of therapeutic gains made in immune checkpoint blockade and CAR-modified T cells, Science awarded cancer immunotherapy its ‘Breakthrough of the Year’ in 2013 [ 56 ]. Subsequently, The Nobel Prize in Physiology or Medicine 2018 awarded discovery of cancer therapy by inhibition of negative immune regulation. These excellent findings laid the foundation for the clinical development of immunotherapy, which have dramatically improved outcomes for many people with cancer. In recent years, lots of immunotherapy drugs, from monoclonal antibody against cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1), to CAR T cell therapy, are approved by U.S. Food and Drug Administration (FDA) for cancer treatment [ 54 – 57 ]. Although no FDA-approved immunotherapies for GBM exists currently, there are several ongoing clinical trials testing in GBM patients, spurred on by advances in immuno-oncology for other tumor types [ 58 ]. Recently, treatment with immune checkpoint inhibitors demonstrated improved OS in some melanoma patients with brain metastases, suggestive of the immunotherapy as a potential treatment option for CNS tumors [ 59 , 60 ]. Despite this, a persistent challenge remain for immunotherapy in treating GBM due to the existence of redundant mechanisms of tumor-mediated immune suppression [ 61 , 62 ]. Besides, molecular heterogeneity in GBM is credited as a major mechanism of therapeutic resistance and therefore an important clinical challenge to develop effective immunotherapeutic directed against GBM [ 63 ]. In addition, adverse events (AEs) with immune-mediated mechanisms are common in patients with advanced solid organ malignancies receiving immunotherapy [ 64 ]. Based on these observations, advancements in immunotherapy for GBM is an exciting direction for the future development of treatments for GBM, but their clinical benefits remain to be seen [ 63 ].

Immune checkpoint blockade

Immune checkpoints exist to dampen or terminate immune activity to guard against autoimmunity and maintain self-tolerance, acting as so-called ‘brakes’ on the immune system. However, tumors can co-opt immune checkpoint pathways to evade immune surveillance. Drugs targeting immune checkpoints, such as CTLA-4, PD-1, and PD-L1 can enhance anti-tumor immune responses and allow T cells to more effectively eradicate cancer cells. Given the success with many solid tumors, the potential of immune checkpoint blockade therapy, has been actively pursued for GBM. Nonetheless, GBM harbour a relatively low number of somatic mutations and lack T-cell infiltration compared with other tumor types [ 65 ], which may limit the availability of immune checkpoint blockade. In this regard, GBM is thought as a type of “cold tumor”. Still, immune checkpoint inhibitors have garnered considerable interest for the treatment of GBM, considering the unique immunologically properties of CNS.

CTLA-4 and PD-1 are negative regulators of T-cell activity that limits immune responses against cancer [ 56 ]. PD-1 binds to its ligands PD-L1, which is expressed in GBM tumors [ 66 , 67 ], and elevated expression levels was shown to correlate with poorer prognoses in some studies [ 67 ]. Ipilimumab is a human anti-CTLA-4 monoclonal antibody (mAb) that blocks CTLA-4 and its ligands (CD80/CD86) with demonstrated efficacy in metastatic melanoma [ 68 ]. Preclinical research has suggested that the combination of CTLA-4 and IL-12 blockade elicits T cell-mediated glioma rejection in a syngeneic murine model of GBM [ 69 ]. A durable survival benefit was achieved utilizing combinatorial blockade against CTLA-4, PD-L1 and indoleamine 2,3 dioxygenase 1 (IDO) in glioma-bearing mice models [ 70 ]. The nivolumab is a fully human immunoglobulin G subclass 4 monoclonal antibody inhibitor of PD-1 approved globally for the treatment of diverse cancers [ 71 ]. Growing studies have demonstrated that the PD-1/PD-L1 axis is immunologically relevant and a therapeutic window exists [ 72 – 74 ]. Taken together, these data provide preclinical evidence that combinatorial targeting immunosuppression may serves as a promising strategy for future clinical trials in patients with GBM. Since immune checkpoint blockade have revolutionized cancer treatment for several solid tumors, there exists the possibility that it can also transform the treatment of GBM. Based on these findings, an early phase I study evaluated the safety/tolerability and efficacy of nivolumab alone or in combination with ipilimumab for patients with recurrent glioblastoma [ 75 ]. In this trial, 40 patients were enrolled from 9 sites in the United States, and exploratory efficacy results indicated that ~ 20% of patients achieved stable disease ≥12 weeks, and 5 (12.5%) survived > 25 months. Additionally, nivolumab monotherapy was better tolerated than nivolumab in combination with ipilimumab and was selected for the phase III cohort (cohort 2) of (CheckMate 143, {"type":"clinical-trial","attrs":{"text":"NCT02017717","term_id":"NCT02017717"}} NCT02017717 ). It should be note that high rates of serious adverse events were observed in nivolumab with ipilimumab, thus this combination strategy is not being pursued further in the phase III stage of this trial. In this phase III trial, the efficacy and safety of nivolumab is being compared with that of bevacizumab (a monoclonal antibody to vascular endothelial growth factor) in patients with recurrent glioblastoma, the preliminary data reported at the 2017 World Federation of Neuro-Oncology Societies meeting revealed that at interim analysis of 369 patients, nivolumab monotherapy did not demonstrate a median OS benefit over bevacizumab (9.8 months with nivolumab versus 10.0 months bevacizumab) [ 45 ]. Although the study did not met the primary end point of OS, no safety concerns were reported [ 76 ]. The results also revealed that patients with methylated MGMT promoter and no baseline corticosteroid dependence may potentially derive benefit from treatment with immune checkpoint blockade [ 76 ]. In a large ongoing randomized phase II trial (CheckMate 548, {"type":"clinical-trial","attrs":{"text":"NCT02667587","term_id":"NCT02667587"}} NCT02667587 ), researchers are investigating nivolumab as an alternative to TMZ (both in combination with radiotherapy) in newly diagnosed GBM patients with methylated MGMT status. A similar ongoing phase III trial for patients with unmethylated MGMT status will also be assigned to receive nivolumab + standard radiotherapy vs. TMZ + standard radiotherapy (CheckMate 498, {"type":"clinical-trial","attrs":{"text":"NCT02617589","term_id":"NCT02617589"}} NCT02617589 ) [ 77 ]. Although the results from these two trials are unpublished at this time, the preliminary data stated by Bristol-Myers Squibb (BMS) at 2019 revealed that CheckMate 548 did not meet one of its primary endpoints and CheckMate 498 did not meet its primary endpoint of OS on final analysis [ 78 ]. Furthermore, a single-arm phase II clinical trial in which neoadjuvant nivolumab was tested in 30 patients with recurrent resectable glioblastoma observed favorable changes in the tumor immune microenvironment ( {"type":"clinical-trial","attrs":{"text":"NCT02550249","term_id":"NCT02550249"}} NCT02550249 ) [ 79 ]. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later [ 79 ]. Moreover, a small randomized phase II clinical trial in this same issue [ 80 ], utilizing neoadjuvant pembrolizumab (a humanized monoclonal antibody that binds the PD-1 receptor) in patients with recurrent resectable glioblastoma described similar intratumoral effects in the immune tissue microenvironment as evidenced by [ 79 ]. The neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may provide a therapeutic window to study the immunobiology of GBM [ 80 ]. Admittedly, these two studies was a small study in which the limited sample size prevents definitive conclusions about the clinical outcome of treatment. To date, clinical trials have revealed that immune checkpoint inhibitors have limit efficacy in GBM, where < 10% of patients show long-term responses. The main reason might be that multiple genomic features are involved in the occurrence and development of GBM, which may determine the response pattern of patients with GBM to checkpoint blockade immunotherapy. To understand the molecular determinants of immunotherapeutic response in GBM, a recent study enrolled 66 patients to investigate the immune and genomic correlates of response to anti-PD-1 immunotherapy in GBM. Genomic and transcriptomic analysis revealed that PTEN mutations are associated with immunosuppressive expression signatures and resistance to immune-checkpoint inhibition, whereas tumors from responders were observed to harbour MAPK pathway alterations ( PTPN11 , BRAF ) [ 81 ]. Of note, a survival difference was seen between responders and non-responders, with a median survival of 14.3 months of responders compared to the 10.1 months of non-responsive patients. Whereas thousands of unselected patients received immune checkpoint inhibitors without evidence of significant response to date, this study showed that a sub-group of patients might benefit from this therapy, suggesting a possibility of personalized, patient-specific GBM treatment.

Beyond that, case reports suggested the effective of anti-PD-1 monotherapy for patients with GBM. Two pediatric patients with recurrent multifocal GBM refractory to current standard therapies exhibited impressive and durable responses to nivolumab [ 82 ]. In addition, an adult patient with germline POLE deficiency who developed a hypermutated glioblastoma showed a clinical response to pembrolizumab [ 83 ]. Notably, the patients with high tumor mutational loads are thought to respond well to immune checkpoint inhibitors in these two reports. Furthermore, in an adult patient with recurrent GBM, treatment with nivolumab resulted in long-term disease control without needing further steroid medication [ 84 ]. While these findings are encouraging, phase III clinical have not demonstrated a clear benefit for single checkpoint inhibitor and no FDA-approved immunotherapy for GBM exists [ 58 ]. Clinical trials outside of GBM have uncovered that a number of biomarkers predict clinical responses to PD-1 axis blockade in cancer therapy [ 85 ]. Well characterized biomarkers including tumor mutational burden [ 86 ] and PD-L1 expression [ 87 ] have been identified in diverse cancer types. Given that the extent of PD-L1 expression in GBM remains the subject of debate [ 45 ], and GBM is typically have a relatively low mutational burden in most cases, a detailed evaluation of validated biomarkers for patient selection and disease surveillance may be particularly important for GBM immunotherapy.

On the horizon: targeting “next-generation” checkpoints

Although CTLA-4 and PD-1 blockade are the focus of the basic research and clinical attention, continued exploration of additional checkpoints may lead to development of combination treatment strategies that can improve responses and expand immune checkpoint blockade to a greater number of GBM patients [ 58 , 77 ].

Unlike the adaptive immune checkpoint PD-L1 who sends to the adaptive immune system a “don’t find me” signal, cluster of differentiation 47 (CD47) sends a “don’t eat me” signal to the innate immune system that blocks macrophages from attacking the tumor [ 88 , 89 ]. The binding of CD47 to its cognate receptor signal-regulatory protein alpha (SIRPα) on phagocytic cells leads to inhibition in the macrophage-mediated tumor cell phagocytosis. Since the recent identification of CD47/SIRPα axis as a therapeutic target for human solid tumors [ 90 – 92 ], there have been several preclinical studies examining the safety and efficacy of targeting CD47 as an immune checkpoint molecule for GBM therapy [ 93 , 94 ]. CD47 blockade by using anti-CD47 antibody was reported to stimulate phagocytosis of glioblastoma by macrophages and hence reduce tumor burden in vivo [ 95 ]. In vitro and in vivo studies demonstrated that CD47 blockade by a humanized anti-CD47 antibody (Hu5F9-G4) enhanced macrophage-mediated phagocytosis, improved survival, and reduced tumor burden in human GBM engrafted mice model [ 92 ]. In vivo study further showed that CD47 blockade could effectively reeducate microglia in the GBM tumor microenvironment to unleash the therapeutic potential of tumor cell phagocytosis [ 96 ]. Additionally, anti-CD47 immunotherapy using Hu5F9-G4 could also be combined with irradiation or TMZ chemotherapy to enhance the therapeutic efficacy of GBM treatment in vitro and in vivo [ 97 ]. Recently, a pre-clinical toxicokinetic study in non-human primates reported no adverse effects associated with Hu5F9-G4. As a matter of fact, CD47 therapeutics including Hu5F9-G4 are moving forward rapidly in the clinic, patients with acute myeloid leukemia (AML) and solid tumors are being recruited for phase I clinical trials ( {"type":"clinical-trial","attrs":{"text":"NCT02678338","term_id":"NCT02678338"}} NCT02678338 and {"type":"clinical-trial","attrs":{"text":"NCT02216409","term_id":"NCT02216409"}} NCT02216409 ) [ 98 , 99 ]. A phase 1b study demonstrated that the combination of Hu5F9-G4 and rituximab produced durable responses in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study ( {"type":"clinical-trial","attrs":{"text":"NCT02953509","term_id":"NCT02953509"}} NCT02953509 ) [ 100 ], and further investigation is ongoing in a phase II trial ( {"type":"clinical-trial","attrs":{"text":"NCT02953509","term_id":"NCT02953509"}} NCT02953509 ). However, no clinical trials have been conducted in GBM to date, the development of CD47 blockade as a therapeutic target either as monotherapy or in combination with other treatments for GBM needs to be studied further.

Despite the achievements of immune checkpoint blockade therapy in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments, suggestive of multiple non-redundant immunosuppressive mechanisms coexist within the tumor microenvironment. One such mechanism is the conversion of inflammatory extracellular adenosine triphosphate (ATP) into immunosuppressive extracellular adenosine (eADO) [ 101 , 102 ]. The canonical pathway is started from the hydrolysis of ATP to AMP by CD39 (also known as ectonucleoside triphosphate diphosphohydrolase 1); non-canonical pathway metabolizes NAD + to ADP-ribose (ADPR) through CD38, which is then processed to AMP by ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (CD203a/PC-1) [ 103 ]. Both pathways converge to CD73 (also known as 5′-nucleotidase), that fully degrades AMP to the final product ADO. Targeting CD73 on host and tumor cells was shown to alleviate adenosine-mediated immunosuppression and to inhibit tumor progression in human solid tumor models [ 104 , 105 ]. Preclinical research revealed that targeted blockade of CD73 could enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 monoclonal antibody [ 106 ]. Across various cancer types, high expression of CD73 has consistently correlated with poor prognosis in patients, thus justifying the rationale to target CD73 in the clinic [ 102 ]. Currently, novel agents targeting the adenosinergic pathway are now reaching clinical trials in patients with advanced cancer either as single agents or in combination with conventional and immunotherapies [ 102 ].

MEDI9447 is a human monoclonal antibody that selectively binds to and inhibits the ectonucleotidase activity of CD73, and the results showed the ability of MEDI9447 in preclinical tumor models [ 107 ]. A phase I trial to test the safety, tolerability, and clinical activity of oleclumab (MEDI9447) alone and in combination with durvalumab (MEDI4736, anti-PD-L1) is currently underway ( {"type":"clinical-trial","attrs":{"text":"NCT02503774","term_id":"NCT02503774"}} NCT02503774 ). Other anti-CD73 monoclonal antibodies, including BMS-986179 ( {"type":"clinical-trial","attrs":{"text":"NCT02754141","term_id":"NCT02754141"}} NCT02754141 ), CPI-006 ( {"type":"clinical-trial","attrs":{"text":"NCT03454451","term_id":"NCT03454451"}} NCT03454451 ) and NZV930 ( {"type":"clinical-trial","attrs":{"text":"NCT03549000","term_id":"NCT03549000"}} NCT03549000 ) have been also actively tested in clinical trials [ 101 ]. Aside from mAbs, novel small-molecule inhibitors of CD73 are being developed and tested as monotherapy or in combination with other immunotherapies in preclinical and clinical trials, such as A001421 [ 94 ], AB680 ( {"type":"clinical-trial","attrs":{"text":"NCT04104672","term_id":"NCT04104672"}} NCT04104672 ), CB-708, and LY3475070 ( {"type":"clinical-trial","attrs":{"text":"NCT04148937","term_id":"NCT04148937"}} NCT04148937 ) [ 101 ]. A001421 have demonstrated profound effects in experimental tumor models when dosed in combination with PD-1 blockade [ 102 ]. Overall, the therapeutic efficacy of these CD73 blockade in patients with cancer is eagerly awaited. With regards to GBM, Preclinical studies showed that CD73 blockade decreases in vitro and in vivo glioblastoma growth and potentiates TMZ induced glioma cytotoxicity [ 108 ]. Further study revealed that blockade of CD73 delays glioblastoma growth by modulating the immune environment [ 109 ]. Of note, immune profiling data from multiple different human tumors and an anti-PD-1 clinical trial in patients with GBM identified CD73 as a specific immunotherapeutic target to improve outcomes for immune checkpoint therapy in glioblastoma multiforme [ 110 ]. The absence of CD73 significantly improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1 [ 110 ], suggestive of CD73 as a combinatorial target in glioblastoma. Although this reverse translational study provide some positive findings of combination immune-checkpoint blockade, it remains to be seen whether the preclinical response observed with combination immune-checkpoint blockade will translate to clinical trials in patients with GBM [ 111 ].

CAR T therapy

Genetic engineering of T cells to express CARs directed against specific antigens of tumor cells has emerged as a promising new treatment for cancer therapy [ 112 ] (Fig. 2 ). CAR are chimeric constructs containing an extracellular domain with tumor-binding moiety, typically a single-chain variable fragment (scFv), followed by a hinge of varying length and flexibility, a transmembrane (TM) region, and one or more intracellular signaling domains associated with the T-cell signaling. First-generation CARs contain the stimulatory domain of CD3ζ, whereas second-generation CARs possess a co-stimulatory domain (typically CD28 or 4-1BB) fused to CD3ζ to ensure full activation. Third-generation CARs consist of two co-stimulatory domains linked to CD3ζ to maximize signaling activation. The first co-stimulatory domain is either a CD28 or a 4-1BB domain, with the second co-stimulatory domain consisting of either a CD28, a 4-1BB or an OX40 domain. The fourth-generation CARs, combine the second-generation CAR with the addition of various genes, including cytokines and co-stimulatory ligands, to enhance the tumoricidal effect of the CAR T cells [ 113 – 115 ] (Fig. (Fig.2). 2 ). Once the modified T cells are administered into the patient, where they can initiate cytotoxic attack on the antigen-bearing tumor cell. Since CAR recognition is either independent on MHC or effective presentation of target epitopes, CAR T therapy has the advantage of bypassing the need for MHC presentation of antigen and development of adaptive immune response [ 115 ].

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General structure of CAR and CAR T-cell therapy. a Basic structure of T-cell receptor (TCR). The TCR comprise variable TCR-α and -β chains coupled to three dimeric signaling transduction modules CD3 δ/ε, CD3 γ/ε and CD3 ζ/ζ. T cell activation usually requires MHC matching. b Structure of 1st- 4th generation CARs. Chimeric antigen receptor (CAR) are fusion proteins consisting of an extracellular domain with a tumor-binding moiety, typically a single-chain variable fragment (scFv), followed by a hinge of varying length and flexibility, a transmembrane (TM) region, and one or more intracellular signaling domains associated with the T-cell signaling. First-generation CARs contain the stimulatory domain of CD3ζ, whereas second-generation CARs possess a co-stimulatory domain (typically CD28 or 4-1BB) fused to CD3ζ to ensure full activation. Third-generation CARs consist of two co-stimulatory domains linked to CD3ζ to maximize signaling activation. The first co-stimulatory domain is either a CD28 or a 4-1BB domain, with the second co-stimulatory domain consisting of either a CD28, a 4-1BB or a OX40 domain. The fourth-generation CARs, combine the second-generation CAR with the addition of various genes, including cytokines and co-stimulatory ligands, to enhance the tumoricidal effect of the CAR T cells. c Mechanisms of CAR-T therapy. CAR-T cells can produce an artificial T cell receptor that has high affinity to a tumor-specific surface antigen. BiTEs can redirect T cells to tumor cell surface antigens and activate T cells. Activated T cells release perforin and other granzymes through immunological synapses. These cytolytic proteins can form pores on tumor cell surface, and thus are endocytosed by tumor cells and then form endosomes and lyse tumor cells ultimately form endosomes in tumor cells and lyse tumor cells ultimately

The clinical potential of CAR T-cell therapy has been most convincingly shown in the field of hematological malignancies [ 116 – 118 ]. Given their extraordinary efficacy in hematological malignancies, efforts have been made to apply CAR T-cell therapies for the treatment of solid tumors including GBM [ 113 , 114 , 119 ]. Recently, several clinical CAR T cell therapies have already been tested for GBM using epidermal growth factor receptor variant III (EGFRvIII), interleukin (IL)13Rα2 (IL-13Ra2), and ephrin-A2 (Her2) as targets, with mixed but informative results [ 120 , 121 ]. Previous clinical study provide promising first-in-human clinical evidence for feasibility of intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing the foundation for further development of this IL13Rα2-specific CAR T cell therapy [ 122 ]. Building on the initial results, Brown et al. [ 123 ] report a case study in which a patient with recurrent multifocal glioblastoma received CAR T cells targeting IL-13Rα2. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding elevated levels of cytokines and immune cells in the cerebrospinal fluid [ 123 ]. The clinical response lasted for 7.5 months after the initiation of CAR T-cell therapy. While the exact cause of relapse remains to be elucidated, instances of tumor recurrence with loss and/or reduced expression of IL13Rα2 has been observed [ 122 , 123 ]. However, this study indicates that in addition to directly targeting tumor cells via IL13Rα2, the CAR T- cells induce an endogenous immune response as increased levels of non-CAR T immune cells and cytokines was observed after each infusion and the treatment was successful in initial tumors despite IL13Rα2 escape. In addition, a phase I dose-escalation study of infusing HER2-CAR-modified autologous virus-specific T cells (VSTs) (HER2-CAR VSTs) in patients with progressive glioblastoma has been conducted [ 124 ]. The data showed that infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive GBM [ 124 ].

In 2017, the results of a first-in-human clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02209376","term_id":"NCT02209376"}} NCT02209376 ) of CART-EGFRvIII in 10 patients with recurrent EGFRvIII-positive GBM were published [ 125 ]. The results demonstrated that manufacturing of CART-EGFRvIII cells from patients with recurrent GBM was safe and feasible. Although no survival benefit was observed from this small study, the authors found that CART-EGFRvIII cells infused intravenously did traffic to the brain tumor and exert antigen-directed activity [ 125 ]. In addition, lower EGFRvIII expressions and the inhibitory tumor microenvironment were also observed post-therapy [ 125 ]. Such antigen escape mechanisms may limit the durability of responses to CAR T therapy. Recently, bispecific T cell engagers (BiTEs) have been proposed as a solution against antigen escape (Fig. (Fig.2) 2 ) [ 126 ]. By engineering EGFR-directed BiTEs, which tether T cells to tumor cells, into the EGFRvIII-CAR T cells, producing a dual-targeted platform to prevent antigen escape. EGFR-targeted BiTEs produced by CAR T cells demonstrated minimal toxicities and antitumor activity against heterogeneous tumors, highlighting a promising avenue for future developments in GBM [ 126 ]. Taken together, these preclinical findings warrant investigation in patients with GBM, which may improve the effectiveness of immunotherapy for this disease [ 127 ]. Despite some encouraging findings, the foremost limitation impeding CAR T therapy for GBM is the heterogeneity in GBM, which make it difficult to develop CAR-based strategies that can target all of the clonal populations [ 78 ]. While this approach requires further validation, modifications to mitigate tumor antigen escape and overcome antigenic heterogeneity might provide a means for effective application of CAR T therapy for GBM treatment.

Oncolytic virotherapy

The concept of virotherapy for malignancies was first demonstrated in a case report in 1912, when DePace described a woman with cervical cancer showed tumor regression after receiving an attenuated rabies virus vaccine. Since then, case studies reporting cancer remission in patients treated with naturally occurring viruses, especially in leukemias and lymphomas [ 128 – 130 ]. However, concerns of serious adverse events and the advent of chemotherapy halted early progress of oncolytic virotherapy [ 131 ]. Its potential was re-evaluated until the end of the twentieth century, supported by the evolution of viral molecular biology, as well as the development of reverse genetics system allowing for virus engineering [ 132 ]. GBM is particularly suitable for oncolytic virus (OV) therapy due to the tumor’s confinement to the brain, lack of distant metastases, and growth being surrounded mainly by post-mitotic cells, which allows for the use of viruses that require active cells cycles for replication [ 133 ].

Now, oncolytic virotherapy represents a promising form of immunotherapy for GBM treatment, which can be divided into two groups: 1) replication-competent OVs that selectively infect and replicate in cancer cells to kill tumor cells; and 2) replication-deficient viral vectors used as delivery vehicles for therapeutic genes. Currently, specific OVs have been genetically engineered to target pathogen-associated receptors present on tumor cells in order to achieve efficient and selective replication. The viral infection and amplification eventually elicit host antitumor immune responses and eliminate cancer cells. To date, over 20 oncolytic virus candidates including Herpes simplex virus Type 1 (HSV-1) [ 134 – 136 ], Adenovirus (Ad) [ 137 ], Reovirus [ 138 ], measles virus (MV) [ 139 , 140 ], Newcastle disease virus [ 141 ], and Poliovirus [ 142 ] have been tested in clinical trials to treat GBM (Table 1 ). In addition, new developments have been also made in delivery techniques for OVs to overcome limitations imposed by the BBB. Recently, Desjardins et al. reported a novel technique for convection enhanced delivery (CED) of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) [ 143 ]. PVSRIPO is a live attenuated poliovirus type 1 (Sabin) vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2 in order to restrict neurovirulence. PVSRIPO targeted GBM through CD155, a high-affinity ligand for the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains, which is broadly upregulated on malignant cells. In the phase I trial ( {"type":"clinical-trial","attrs":{"text":"NCT01491893","term_id":"NCT01491893"}} NCT01491893 ), intratumoral CED of PVSRIPO in patients with recurrent GBM confirmed the absence of neurovirulent potential, and was granted breakthrough-therapy designation by FDA in May 2016. Preliminary data have revealed that the survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. On the basis of phase I findings, the phase II randomized trial ( {"type":"clinical-trial","attrs":{"text":"NCT02986178","term_id":"NCT02986178"}} NCT02986178 ) of PVSRIPO alone or in combination with single-cycle lomustine in patients with recurrent GBM are underway. The therapeutic efficacy of this novel treatment modality in patients with GBM is eagerly awaited.

Summary of clinical trials of oncolytic viral therapy for patients with glioblastoma

Most data were obtained from findings from www.clinicaltrials.gov using the search terms “glioblastoma” and “oncolytic”; 5-FC 5-flucytosine, TMZ temozolomide, OS overall survival, ORR objective response rate, IFN-γ interferon Gamma, SOC Standard of Care, DLT dose limiting toxicities, AE adverse event, MTD maximum tolerated dose, PFS progression-free survival, HSV herpes simplex virus, CED convection-enhanced delivery, NSC neural stem cells, RP2D recommended phase 2 dose, ORR objective radiographic response, DORR duration of objective radiographic response

Since the first application of virus engineering to an oncolytic HSV in murine glioblastoma models [ 144 ], the pace of clinical activities has accelerated considerably [ 145 ], with numerous ongoing or completed trials using modified HSV constructs (Table (Table1). 1 ). Trials including G207 ( {"type":"clinical-trial","attrs":{"text":"NCT00028158","term_id":"NCT00028158"}} NCT00028158 , {"type":"clinical-trial","attrs":{"text":"NCT03911388","term_id":"NCT03911388"}} NCT03911388 and {"type":"clinical-trial","attrs":{"text":"NCT02457845","term_id":"NCT02457845"}} NCT02457845 ), HSV-1716 ( {"type":"clinical-trial","attrs":{"text":"NCT02031965","term_id":"NCT02031965"}} NCT02031965 ), M032 ( {"type":"clinical-trial","attrs":{"text":"NCT02062827","term_id":"NCT02062827"}} NCT02062827 ), MVR-C252 ( {"type":"clinical-trial","attrs":{"text":"NCT05095441","term_id":"NCT05095441"}} NCT05095441 ), C134 ( {"type":"clinical-trial","attrs":{"text":"NCT03657576","term_id":"NCT03657576"}} NCT03657576 ) have been conducted or are ongoing in patients with GBM. G47Δ, a third-generation oncolytic HSV-1, has been tested in a Phase I–IIa trial (UMIN-CTR: UMIN000002661) for GBM patients in Japan and demonstrated the safety of G47Δ inoculated into the human brain. The subsequent investigator-initiated phase II clinical trial (UMIN-CTR: UMIN000015995) in patients with GBM has recently been completed with good results [ 146 ]. Base on the positive results from this phase II trial, G47∆ (Delytact/Teserpaturev) got conditional and time-limited approval for the treatment of malignant gliomas in Japan at June 2021. Additionally, several phase I and II trials, including ( {"type":"clinical-trial","attrs":{"text":"NCT02197169","term_id":"NCT02197169"}} NCT02197169 ), ( {"type":"clinical-trial","attrs":{"text":"NCT01956734","term_id":"NCT01956734"}} NCT01956734 ), ( {"type":"clinical-trial","attrs":{"text":"NCT03896568","term_id":"NCT03896568"}} NCT03896568 ), ( {"type":"clinical-trial","attrs":{"text":"NCT01582516","term_id":"NCT01582516"}} NCT01582516 ), and ( {"type":"clinical-trial","attrs":{"text":"NCT02798406","term_id":"NCT02798406"}} NCT02798406 ) using genetically engineered oncolytic adenovirus combined with standard-of-care or immune checkpoint blockade are currently ongoing for patients with GBM (Table (Table1) 1 ) and are given expectations to bring positive outcomes. Adenoviruses have also been modified to aglatimagene besadenovec (AdV-tk), an adenoviral vector containing the HSV thymidine kinase gene, followed by an antiherpetic prodrug such as valacyclovir, which functions as toxic nucleotide analogue that can kill tumor cells [ 147 ]. This approach, termed gene-mediated cytotoxic immunotherapy, was reported to be safe in newly diagnosed malignant gliomas in the phase I b clinical trial [ 148 ]. Subsequently, the phase II trial ( {"type":"clinical-trial","attrs":{"text":"NCT00589875","term_id":"NCT00589875"}} NCT00589875 ) have been conducted and demonstrated notably improved survival outcomes for malignant gliomas associated with AdV-tk-based therapy [ 147 ] (Table (Table1). 1 ). The clinical trials proved the safety and efficacy of OV therapy for GBM, but very few progressed to phase III trials. Previously, a phase III trial ASPECT (registered with EudraCT, number 2004–000464-28) assessed the efficacy and safety of adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir in patients with newly diagnosed resectable GBM. The ASPECT found no significant effect on OS [ 149 ]. Recently, a phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT02414165","term_id":"NCT02414165"}} NCT02414165 ) of Toca511 & Toca FC was terminated for unknown reasons. Toca 511 consists of a purified retroviral replicating vector encoding a modified yeast cytosine deaminase (CD) gene. The CD gene converts the 5-flucytosine (5-FC) to the anticancer drug 5-FU in tumor cells that have been infected by the Toca 511 vector. Notably, several phase III trials for cancer immunotherapies combined with OVs have shown clinical promise for diverse cancers [ 150 ]. Oncolytic virotherapy for GBM remains promising and may impact the future of patient care. Recent studies have shown that Zika virus (ZIKV) has oncolytic activity against GSCs, suggesting that engineering of ZIKV may provide a therapeutic modality against Glioblastoma [ 151 – 155 ]. As ZIKV selectively infects and kills GSCs relative to normal neuronal cells, it may be an option to serves as a candidate for GBM therapy. Of note, despite the general safety of OV application confirmed by preclinical and clinical trials, the moderate clinical efficacy has not yet matched the preclinical promise from laboratory experiments.

Vaccine therapy

Cancer vaccine therapy has shown great promise with both preventive and therapeutic potentials [ 156 , 157 ]. For GBM, cancer vaccines is designed to target tumor-associated antigens to induce an immune response against tumors. Given that GBM-specific antigens are rare, GBM antigen targets are most often tumor-associated antigens, which limiting patient inclusion. To date, only a few vaccination approaches have reached phase III clinical testing in patients with GBM, and numerous others are at earlier stages of clinical development. The best studied tumor-specific antigen is EGFRvIII, which is a constitutively active mutant form of EGFR only expressed in 25–30% of GBM [ 158 ].

Rindopepimut (also known as CDX-110), a peptide vaccine targeting EGFRvIII has been tested in several clinical trials. In three uncontrolled phase II studies, rindopepimut vaccination in GBM patients with gross total resection and chemoradiotherapy have provided evidence of improved median survival of 24 months compared with historical controls [ 159 – 161 ]. Following these encouraging findings, an international phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT01480479","term_id":"NCT01480479"}} NCT01480479 ), ACT IV was conducted to further assess the efficacy of rindopepimut in newly diagnosed patients with EGFRvIII-positive GBM. Despite the strong anti-EGFRvIII immune response generated in patients, the primary study analysis did not show a survival benefit for patients with minimal residual disease who received rindopepimut with TMZ versus those who received TMZ alone [ 162 ]. Of note, the spontaneous loss of antigen was seen in both the treatment and control arm, questioning the utility of immunotherapy targeting a single tumor antigen with heterogeneous tumor expression [ 162 ]. Recent evidence from a double-blind, randomized, phase II study ( {"type":"clinical-trial","attrs":{"text":"NCT01498328","term_id":"NCT01498328"}} NCT01498328 ) in a smaller cohort of patients with recurrent EGFRvIII-positive GBM suggested favorable outcomes for rindopepimut when combined with standard bevacizumab versus bevacizumab alone [ 163 ]. Taken together, the positive results with rindopepimut in recurrent GBM in ReACT and the negative results of ACT IV in newly diagnosed GBM lend support to further clinical trials that use combination strategies such as immunotherapy with angiogenesis inhibition.

ICT107 is a six synthetic peptide stimulated DC vaccine specifically designed for GBM, which has also reached to phase III clinical trials. A phase I study demonstrated the safety of ICT-107 with a suggestion of benefit to patients who were HLA-A2 positive [ 164 ]. A phase II trial showed that ICT-107 has some therapeutic activity in HLA-A2 positive patients and led to a phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT02546102","term_id":"NCT02546102"}} NCT02546102 ) in HLA-A2 + newly diagnosed patients with GBM. But this phase III trial was suspended in 2017 due to lack of funding. DCVaxL, a dendritic cell-based vaccine therapy which use whole tumor lysate to pulse patient-derived DCs. Given the promising result in preclinical models and early stage clinical trials [ 165 , 166 ], a phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT00045968","term_id":"NCT00045968"}} NCT00045968 ) of DCVax-L was conducted in newly diagnosed GBM. In this trial, the overall intent-to-treat population had a median OS of 23.1 months which is superior to median OS of 15–17 months from past studies and clinical practice [ 167 ]. However, this trial was subsequently dropped for unidentified reasons. To summarize, current results from the clinical trials on vaccines for GBM are not very promising, lack of GBM-specific antigen and high heterogeneity of the tumors pose challenges to GBM vaccine therapy.

Recently, advances in next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumor neoantigens, which are derived from somatic mutations of the tumor and are therefore tumor specific [ 157 , 168 ]. Neoantigens are highly specific for individual patients and hence, tumor vaccines targeting neoantigens can effectively trigger de novo T cell responses against neoantigens, thereby achieving personalized precision treatment. Initial studies of personalized neoantigen-based vaccines have demonstrated robust tumor-specific immunogenicity and preliminary evidence of anti-tumor activity in patients with high-risk melanoma and other cancers [ 168 ]. Based on the encouraging findings, a phase I/Ib study of personalized neoantigen vaccines has been tested in 10 patients with newly diagnosed MGMT -unmethylated GBM following surgical resection and conventional radiotherapy. Patients who did not receive dexamethasone generated circulating polyfunctional neoantigen-specific CD4 + and CD8 + T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumor-infiltrating T cells [ 169 ]. Despite generating systemic and intratumoral neoantigen-specific immune responses post-vaccination, all patients showed tumor recurrence and ultimately died of progressive disease, indicating that the induced T cell responses must still overcome considerable challenges to produce clinically relevant anti-tumor activity, including tumor-intrinsic defects and immunosuppressive factors in the microenvironment [ 169 ]. Given that neoantigen-targeting vaccines have the potential to favorably alter the immune milieu of glioblastoma, thus, combining vaccination with other regimens such as immune checkpoint inhibition may be beneficial.

Focused ultrasound therapy

Despite incremental advances in the therapeutic approach to GBM, there has been minimal development of both new and existing drug therapies for recurrent GBM [ 6 ]. The last drug to significantly improve OS for GBM was TMZ, which was introduced 20 years ago [ 35 ]. After decades of development, bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) was granted accelerated FDA approval for recurrent GBM without the completion of a randomized Phase III trial, making bevacizumab the third FDA-approved treatment for GBM [ 170 ]. Subsequently, bevacizumab was tested in two large randomized phase III trials ( {"type":"clinical-trial","attrs":{"text":"NCT00884741","term_id":"NCT00884741"}} NCT00884741 and {"type":"clinical-trial","attrs":{"text":"NCT00943826","term_id":"NCT00943826"}} NCT00943826 ) [ 10 , 11 ]. Despite improvement in median progression-free survival (PFS) of both trials, first-line use of bevacizumab did not improve OS in patients with glioblastoma. Consistent with this, according to a systematic analysis, the combination of bevacizumab for newly diagnosed GBM is beneficial in terms of prolonging median PFS but not OS [ 171 ]. Thus, innovative therapies are needed to ultimately improve the outcome of patients with glioblastoma. One of the major limitations of new GBM therapies in part because of inefficient drug delivery across the BBB. The BBB is formed by brain endothelial cells lining the cerebral microvasculature, presents a particular challenge for drug delivery [ 34 ]. Recently, focused ultrasound to overcome the BBB has led to the emergence of this technology as a viable new option for targeted delivery to the CNS [ 172 ]. Preclinical studies have showed that low-intensity pulsed ultrasound increased the concentrations of systemically administered drug therapies in the brain parenchyma in animal models and prolonged survival in GBM preclinical models [ 31 , 33 , 173 – 177 ].

After several decades of pre-clinical research, focused ultrasound has recently translated into clinical studies for GBM [ 178 ]. In 2016, a first-in-man, single-arm, single-center trial ( {"type":"clinical-trial","attrs":{"text":"NCT02253212","term_id":"NCT02253212"}} NCT02253212 ) was initiated to evaluate the safety and feasibility of repeated pulsed ultrasound in recurrent GBM [ 34 ]. The results showed that focused ultrasound as a new technique for treating patients with GBM was safe and not burdensome [ 34 , 35 ]. More importantly, the pulsed ultrasound add-on treatment presented in this work can be extended and combined with other therapies to enhance drug penetration in patients with GBM [ 35 ]. A prospective single-arm, open-label trial was conducted to investigate serial magnetic resonance-guided focused ultrasound (MRgFUS) and adjuvant TMZ combination in patients with GBM ( {"type":"clinical-trial","attrs":{"text":"NCT03616860","term_id":"NCT03616860"}} NCT03616860 ). This first-in-human proof-of-concept study showed that MRgFUS enriches the signal of circulating brain-derived biomarkers, providing data for the feasibility of a focused ultrasound framework to liquid biopsy in neuro-oncology patients [ 179 ]. Transient BBB opening in tumor using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was reported to be safe and feasible ( {"type":"clinical-trial","attrs":{"text":"NCT02343991","term_id":"NCT02343991"}} NCT02343991 ) [ 180 ].

In addition, several clinical trials including ( {"type":"clinical-trial","attrs":{"text":"NCT04998864","term_id":"NCT04998864"}} NCT04998864 ), ( {"type":"clinical-trial","attrs":{"text":"NCT04988750","term_id":"NCT04988750"}} NCT04988750 ), and ( {"type":"clinical-trial","attrs":{"text":"NCT04446416","term_id":"NCT04446416"}} NCT04446416 ) to evaluate the safety and preliminary efficacy of focused ultrasound are underway.

Conclusions and perspectives

Immunotherapy has already demonstrated safety and feasibility for a variety of malignancies, its efficacy in clinical trials for glioblastoma remain to be investigated. Currently, standard therapy consists of tumor resection followed by radiotherapy and concomitant TMZ are still the mainstay of treatment, all of which have immunosuppressive effects. Besides, the glioblastoma microenvironment is a hostile attribution for anti-tumor immune responses, we must be cognizant of this complexity when developing immunotherapies. Hence, combination approaches with the aim of making these “cold” tumors “hot” are urgently needed and thus augmenting current immunotherapy strategies. Although immunotherapy represents a rapidly developing frontier in GBM therapy, consistent and sustained responses remain rare. There are still many challenges including: (i) local immunosuppression in the microenvironment after treatments which made the efficacy being modest and limited to a minority of patients; (ii) deficiency of specific tumor antigens and high tumor heterogeneity within GBM; (iii) chronic immune toxicities and the long-term implications of these effects associated with immunotherapy. Despite the encouraging results of preclinical and phase I/II clinical trials, even successful in a few case reports, the phase II/III transition remains particularly challenging, no successful phase III clinical trials with large patient cohorts for GBM immunotherapy have been reported so far.

Given that immunotherapy and conventional treatment act on different targets, synergistic or combined treatment may achieve greater therapeutic outcomes. However, intense research and clinical development are required to optimize the available treatment options and to overcome potential side effects. The success of this strategy includes the use of validated biomarkers, appropriate patient selection criteria, strategies to prevent adverse events, and the implementation of immunotherapy in multimodal treatment approach together with conventional therapies. Immunotherapy strategies based on well-known checkpoint blockades have shown promising activity against GBM in preclinical models and some case reports, whereas the results emerging from clinical trials with large patient cohorts are disappointing. The main reason might be that multiple genomic and epigenetic features are involved in the development of GBM, which may determine the response pattern of patients with GBM to checkpoint blockade-based immunotherapy. Therefore, a deeper understanding of the molecular pathology of GBM, tumor-intrinsic dominant signaling pathways driving tumorigenesis that are candidates to become therapeutic targets and tumor-specific antigenic profiles more effectively are urgently needed. Given that the heterogeneity across patients often lead to failure with immunotherapy, adding other therapeutic modalities such as molecular targeted therapy to immunotherapy may create new avenues for success. Combining immune checkpoint therapy with these novel agents may even further clinical activity of the PD-1 and CTLA-4 blockades. In addition, targeting “next generation” checkpoints is warranted as a single agent or in combination with other immunomodulatory approaches for GBM. Future treatments will likely consist of checkpoint blockade with addition of individualized therapy on the basis of tumor subtype and site of metastatic disease.

CAR T-based immunotherapy represents a promising therapeutic approach, but antigenic heterogeneity and restoration of immunosuppressive milieu post-therapy may limit the durability of responses to CAR T therapy. Identification of stably expressed and sufficiently tumor-specific antigens and agents that target immunosuppressive molecules are required to overcome the barrier. Recently, BiTEs have been tested in preclinical studies as a solution against antigen escape, it remain to be determined to successfully translate the new molecular findings into improved clinical management. Oncolytic viruses might exert pro-inflammatory responses, thus providing a potential to overcome the immunosuppression of glioblastoma. The future direction of oncolytic viral therapies seems to be focused on combinations with other immunotherapy strategies, in the hope of exploiting the potentially durable anticancer immune responses initiated by the viral infection to elicit prolonged clinical responses. Based on this, a combination of CAR T and OVs may benefit mutually. OV infection induces local inflammation and attracts T cells to tumors, which can reinforce the attraction of CAR T cells in TME [ 181 ]. Despite the promise of this combination approach, the main impediment to this strategy is the rapid clearance of OVs, presenting a challenge to clinical practice in future [ 182 ]. Vaccine therapy has been considered one of the most promising approaches to improve the outcomes of patients with GBM, but data from the clinical trials GBM are disappointing. Given that the lack of high expression of GBM-specific antigens are limiting factors in the development of peptide vaccine-based strategies, personalized neoantigen-based vaccines have attracted much attention in GBM vaccine therapy, although its clinical efficacy requires further investigation. To summarize, the experiences that have been gathered with immunotherapy for GBM is generally insufficient to translate into significant clinical benefit, combinatorial approaches might provide superior results. Despite the challenges and disappointing clinical results existed in developing immunotherapy for GBM, pursuing this path is justified given not only the therapeutic potential of this treatment, but also given the accelerating rate of progress. Additionally, the clinical realities of the contribution of the BBB to treatment failure in GBM argue for renewed efforts to optimize BBB-disruption technologies, develop BBB-penetrating agents, and refine implantable drug delivery technologies that bypass the BBB [ 183 ].

Acknowledgements

We thank all the researchers whose works have contributed to the topics and been cited in this review paper. Regrettably, we apologize to those authors whose excellent work could not be cited due to space limitations.

Abbreviations

Authors’ contributions.

ZZZ designed the study; ZZZ, LR and NL did the literature search; ZZZ and LR wrote the manuscript; ZZZ and LR prepared the tables and figures; ZZZ revised the manuscript; All authors read and approved the final version of the manuscript.

This work was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001) and the National Natural Science Foundation of China (31700150). The funding agencies did not involve in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the paper for publication.

Availability of data and materials

Declarations.

All authors consent to publication.

The author declare that there is no conflict of interests regarding the publication of this paper.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Powerful chemotherapy drug reaches brain tumors using novel ultrasound technology

Feinberg School of Medicine

A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can’t permeate the blood-brain barrier to reach the aggressive brain tumor.

But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.

The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.

Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.

In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

“This is potentially a huge advance for glioblastoma patients,” said lead investigator Dr. Adam Sonabend , an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.

Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.

The paper was published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.

In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour

The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.

“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” said Sonabend, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.

In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.

Clinical trial for patients with recurrent glioblastoma

The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial — in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique — is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.

Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent dye called fluorescein and by MRI obtained after ultrasound therapy.

“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.

Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp.

The work is funded by the National Cancer Institute of the National Institutes of Health, the Lou and Jean Malnati Brain Tumor Institute of the Lurie Cancer Center and SPORE support from the Moceri Family Foundation and the Panattoni family.

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New treatment merges two technologies to fight brain cancer.

Bioadhesive nanoparticles within human glioma tumor cells.

A new treatment developed by Yale researchers uses bioadhesive nanoparticles that adhere to the site of the tumor and then slowly release the synthesized peptide nucleic acids that they’re carrying. In this image, the nanoparticles (red) are visible within human glioma tumor cells (green with blue nuclei).

A team of researchers from Yale and the University of Connecticut (UConn) has developed a nanoparticle-based treatment that targets multiple culprits in glioblastoma, a particularly aggressive and deadly form of brain cancer.

The results are published Feb. 8 in Science Advances.

The new treatment uses bioadhesive nanoparticles that adhere to the site of the tumor and then slowly release the synthesized peptide nucleic acids that they’re carrying. These peptide nucleic acids target certain microRNAs — that is, short strands of RNA that play a role in gene expression. Specifically, they’re directed at a type of overexpressed microRNA known as “oncomiRs” that lead to the proliferation of cancer cells and growth of the tumor. When the peptide nucleic acids attach to the oncomiRs, they stop the tumor-promoting activity.

The laboratories of professors Mark Saltzman of Yale and Raman Bahal of the University of Connecticut collaborated on the treatment system. Unlike similar efforts that target only one oncomiR at a time, this treatment targets two, making its effect on cancer cells stronger, the researchers say. The test mice who received the treatment lived for a significantly longer time than the control mice.

“ The treatment can knock down both targets at the same time, which turns out to have a remarkably more powerful result, as we saw with the increased survival results,” said Saltzman, the Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology and member of Yale Cancer Center. “These results are the best I've ever seen in this sort of aggressive brain tumor.”

One challenge in developing the treatment was designing the anti-cancer agents, known as antimiRs, so that two different ones could fit in a single nanoparticle.

“ We synthesized all these compounds and came up with the idea that you don't have to target one oncomiR at a time,” said Bahal, associate professor of pharmaceutics at UConn. “Now we can think about multiple oncomiR targets.”

For this work, the researchers targeted the oncomiRs known as miR-10b and miR-21, which are both very common in glioblastoma. Future treatments, though, can be easily tailored for specific patients. For instance, if a biopsy of a patient’s tumor produces a profile showing the proliferation of different oncomiRs, the treatment could be appropriately altered.

Saltzman calls the treatment “a marriage of two technologies.”

“ One is the bioadhesive nanoparticle technology, which we had developed earlier, and marrying it to this peptide nucleic acid technology that Raman has perfected,” he said.

Because the treatment is localized to the tumor site, Bahal noted that both the synthesized nucleic acids and the nanoparticles that deliver them to the tumor site are nontoxic. Also critical to the treatment’s success is that the particles and the agent it releases remain at the tumor site for about 40 days. Conventional site-specific treatments tend to wash away fairly quickly.

“ These are high-binding molecules that are scalable and effective simultaneously,” Bahal said. “It’s targeted and stays there. Traditional molecules have had many challenges in terms of toxicity.”

Ideally, the delivery system would be applied as part of a larger treatment regimen.

“ We designed it to be an add-on to what physicians do already,” Saltzman said. “They would do a surgery, then they infuse our nanoparticles, and then they give chemotherapy and/or radiation in the way that they normally do. We're expecting that this would lead to a better result because the nanoparticle/anti-microRNA is sensitizing the cells to the chemotherapy and the radiation therapy.”

The study’s other authors are, from Yale, Yazhe Wang, Hee-Won Suh, Yong Xiao, Yanxiang Deng, Rong Fan, Anita Huttner, and Ranjit S. Bindra; and from UConn, Shipra Malik and Vijender Singh.

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Experimental vaccine shows promise in delaying the return of aggressive brain tumor

John Wishman was diagnosed with the deadliest form of brain cancer, glioblastoma , in fall 2020.

Two and a half years later, he’s still traveling and enjoying life — a rarity for a cancer with an average survival time of just 12 to 18 months.

Wishman, 61, of Buffalo, New York, attributes that to an experimental vaccine that’s designed to delay the progression of the tumor. The vaccine, called SurVaxM, targets a protein found in tumors called survivin, named for the role it’s thought to play in the survival of cancer cells. Get rid of survivin, the thinking goes, and the cancer cells will die.

It sounds like a far-fetched dream: a vaccine that can delay the return of glioblastoma, one of the deadliest and treatment-resistant cancers. More than 14,000 people in the U.S. were diagnosed last year, according to Tom Halkin, a spokesperson for the National Brain Tumor Society , a nonprofit group. It accounts for almost half of all malignant brain tumors. The disease is devastating for patients and families; the five-year survival rate is 6.8%.

Wishman got the vaccine through an expanded access program — sometimes called compassionate use — that allows seriously ill patients to gain access to experimental medicines. His daughter Lydia is a nurse at Roswell Park Comprehensive Cancer Center, where researchers are studying the drug.

In an early clinical trial, SurVaxM was found to extend survival time for people diagnosed with the brain cancer to 26 months, on average. Now the drugmaker, New York-based MimiVax, is enrolling patients in a larger trial, hoping to confirm the results. The expanded access program is no longer available.

The new trial will enroll up to 270 patients. It is expected to take place at more than 10 sites in the U.S. and China and will compare the shot to patients who receive standard care.

Tracey Kassman, 65, enrolled in April 2022, three months after being diagnosed with glioblastoma. That same month, she received her first shot.

Kassman, a retired lawyer from Buffalo, now gets a shot once every two months. But because the trial is randomized and double-blinded, neither Kassman nor her doctors know if she’s getting the vaccine or a placebo.

“It’s been at times a leap of faith,” she said, “because right before I get the shot, I have this MRI, and every time I have the MRI, I’m like, ‘OK, well this could be it.’”

Why is glioblastoma so hard to treat?

Glioblastomas are aggressive cancers: They grow quickly and tend to have invaded other parts of the brain and spinal cord by the time a person is diagnosed.

Surgical removal of the entire tumor is almost impossible.

“It’s like octopus tentacles reaching into other parts of the brain,” said Honggang Cui, an associate professor of chemical and biomolecular engineering at Johns Hopkins Whiting School of Engineering.

Treatment typically involves surgery, chemotherapy and radiation, Cui said. But unless every cancer cell is eliminated, the tumor often comes back in what’s referred to as recurrence.

SurVaxM works by training the immune system to target and attack the cancer cells, so if they do return, the body can pick them off, preventing a new tumor from growing, said Michael Ciesielski, the CEO of MimiVax.

Tracey Kassman was diagnosed with glioblastoma in January 2022.

The approach is “promising,” Cui said. “This could bring hope to people who are impacted by GBM.”

Participants in the trial will first have surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy, with a drug called temozolomide, said Dr. Robert Fenstermaker, the chair of the neurosurgery department at the Roswell Park Comprehensive Cancer Center and co-creator of SurVaxM.

“There’s usually a hiatus of about a month while radiation is still working, and it’s during that phase that we like to start the vaccination because that’s when the immune system has been rejuvenated,” he said.

The vaccine — given in the arm just like a flu shot or Covid shot — consists of four doses, spread out over two months, followed by a booster dose every two months. Participants in the trial will either get the real vaccine for each shot or a shot of a placebo every time. Participants will also get a brain scan every two months to monitor for signs of progression.

A need for different approaches

SurVaxM isn’t the first attempt to create a vaccine to delay the recurrence of glioblastoma. Other cancer vaccines have targeted survivin, but none of them so far have reached mid- to late-stage clinical trials, according to Ciesielski.

Dr. Alyx Porter, a neuro-oncologist at the Mayo Clinic in Phoenix, said the approach is different from what’s been tried in the past.

Targeted therapies like checkpoint inhibitors , for example, have grown in popularity in recent years, improving survival in people with cancer including those with breast or lung cancers. But these drugs are far less effective for brain tumors, because they can’t cross the blood-brain barrier, a network of blood vessels that keeps foreign substances from entering the brain.

The belief, Porter said, is that the antibodies generated by a vaccine would be able to reach the brain. But, she added, “the proof will be in the pudding with the trial.”

Results are still a ways off: According to Ciesielski, the company doesn’t expect its earliest results from the Phase 2b trial until mid-2024, and the trial likely won’t be completed for another 18 to 24 months after that. If successful, the company will have to conduct a larger Phase 3 clinical trial.

The high mortality rates of glioblastoma “warrants people pressing the edge and seeking out new treatments and allowing us to really maximize where immunotherapy may benefit,” said Porter, who is not involved with the SurVaxM trial.

So far, the drug appears to be safe, Fenstermaker said. Known side effects from the vaccine include fever, itching, redness and muscle aches.

Ciesielski said the company is also looking to use the vaccine on other forms of cancer, including multiple myeloma and neuroendocrine tumors , a rare form of cancer that can develop wherever there are neuroendocrine cells, which are found in various organs including the lungs, pancreas and gastrointestinal tract.

For Kassman, of Buffalo, New York, she feels “incredibly lucky” for a chance at a possible treatment.

“I could have ignored this whole thing again for a couple of weeks,” she said, “and I might not be here to talk about this with you.”

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Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

Open access
Published: 15 April 2022

Emerging therapies for glioblastoma: current state and future directions

Liang Rong 1 ,
Ni Li 1 &
Zhenzhen Zhang ORCID: orcid.org/0000-0002-9885-7453 2

Journal of Experimental & Clinical Cancer Research volume 41 , Article number: 142 ( 2022 ) Cite this article

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Gliomas account for almost 30% of primary brain tumors and 80% of all malignant ones. Based on their histopathological features, gliomas are traditionally classified by the World Health Organization (WHO) as grade I and II (low-grade gliomas), grade III (anaplastic) and IV (glioblastoma) [ 1 ], which indicate different degrees of malignancy. In recent years, with the development of genomic, transcriptomic and epigenetic profiling, substantial advances have been achieved in new concepts of classifying and treating gliomas [ 2 , 3 , 4 , 5 , 6 ] (Fig. 1 ), which will complement the morphology-alone-based classification. The classification of molecular subtypes within the glioma facilitates molecular diagnosis in a timely manner to offer opportunities to select the proper treatment modality according to the demand of clinical practice [ 7 ]. Glioblastoma (GBM) is the most common and aggressive type of primary brain tumors, which comprises up to 50% of all gliomas. Despite progress made in the current standard of care including surgery, radiotherapy, and pharmacotherapy (typically chemotherapy with concomitant temozolomide (TMZ)), the outcome for patients remains almost universally lethal [ 2 ], with a median overall survival (OS) ranging from 14.6 to 20.5 months [ 8 , 9 , 10 , 11 , 12 ]. The prognosis is much worse in elderly patients, who have an average survival from diagnosis of less than 8.5 months [ 13 ]. Given the poor survival with currently approved treatments for GBM, new therapeutic strategies are urgently needed.

For most patients with GBM, there is no known causative factors for this disease. The only well-established exogenous environmental cause of glioma is exposure to high doses of ionizing radiation [ 14 , 15 ]. Other risks including viral triggers (human cytomegalovirus) [ 16 ], obesity during adolescence [ 17 ], and family history of cancer [ 18 ] are continuing to be explored. Recent research has focused on identifying germline polymorphisms associated with risk of glioma, and reveals that genetic factors determine the degree of risk from these exposures [ 15 ]. Despite much efforts, little progress has been made in the survival outcomes of patients with GBM. The treatments fail mainly due to the unique molecular characteristics of GBM. Especially, the presence of a population of stem-like cells called glioma stem cells (GSCs) with ability of self-renewal and tumorigenicity, making it resistant to chemotherapy and radiotherapy [ 19 , 20 ]. GBM cells have the propensity to infiltrate/invade into the adjacent normal brain tissues of tumor and along blood vessels, which prevents complete resection of the tumor and limits the effect of local radiotherapy [ 21 ]. Other features of GBM contributing to poor prognosis include: 1) the existence of the blood-brain barrier (BBB), 2) the relative immune privileged status of the central nervous system (CNS). Thus, precise strategies based on tumor-intrinsic dominant signaling pathways and tumor-specific antigenic profiles may ultimately improve outcomes for GBM patients. Fortunately, advances in decades of investment in molecular pathogenesis of glioblastoma are rapidly translated into innovative clinical trials, utilizing improved genomic, epigenetic, transcriptomic and proteomic characterization of glioblastoma as well as the brain microenvironment and immune system interactions [ 22 ]. With these encouraging findings, immunotherapy including immune checkpoint blockade, chimeric antigen receptor T (CAR-T) cell therapy, oncolytic virotherapy and vaccine therapy have been actively tested in clinical trials for GBM [ 23 ]. Studies are ongoing to use combinatorial therapy with the aim of reducing adverse effects and enhancing antitumor responses [ 24 , 25 , 26 ]. Moreover, emerging insights into BBB features have yielded novel strategies to improve drug penetration into the tumor and infiltrative regions [ 27 ]. On the basis of preclinical work [ 28 , 29 , 30 , 31 , 32 , 33 ], focused ultrasound therapy have been tested in clinical trials and achieved improved treatment outcomes in patients with recurrent GBM [ 34 , 35 ], opening avenues for the development of innovative combinatorial strategies for targeting GBM. Herein, we set forth the rationales for these promising therapies in treating GBM, review the potential therapeutic targets, the current status of pre-clinical and clinical trials, and discuss the challenges and future directions of emerging therapies.

The CNS is an immunologically distinct site

Current standard of care and immunotherapy

GBM is currently incurable because of its high recurrence after standard multimodality treatment, including surgery to remove the main tumor followed by concomitant radiation and adjuvant TMZ chemotherapy to target residual tumor cells. Because of the presence of GSCs, it requires complete destruction of the tumor, even a miniscule amount of residual tumor can lead to fatal recurrence [ 46 ]. Recently, intraoperative imaging techniques to maximize extent of resection have contributed considerably in defining the margins of glioblastoma [ 47 , 48 ]. However, radical extirpation of the tumor is not possible due to infiltration of the tumor into the surrounding brain, the role of image-guided surgery in maximizing extent of resection remains uncertain [ 46 ]. Currently, TMZ replaced nitrosoureas as the standard for patients with newly diagnosed GBM. To a certain extent, the success of this strategy depends on the methylation status of O-6 methylguanine-DNA methyl-guanine-methyltransferase ( MGMT ) [ 13 ]. In agreement to this, a Phase III trial demonstrated that GBM patients with MGMT promoter methylation achieved higher survival rates than patients with unmethylated MGMT promoter [ 49 ]. Subsequently, a randomized Phase III trial (NCT00006353) in elderly GBM patients confirmed that patients with MGMT promoter methylation benefitted more from adjuvant TMZ with radiotherapy than radiotherapy alone [ 49 ], suggesting that the benefit seen in patients with MGMT promoter methylation may possibly correlated to addition of TMZ. Radiotherapy remains the primary treatment modality in unresectable GBM. Radiotherapy is usually combined with chemotherapy following surgery in different sequential combinations. According to a systematic review of randomized clinical trials, radiotherapy plus TMZ provides better survival outcomes than radiotherapy alone in treating GBM [ 50 ]. Recently, A multi-institutional GBM-molRPA cohort reported that conventionally fractionated standard radiotherapy significantly prolonged OS than short-course radiotherapy in selected elderly GBM patients treated with TMZ-based chemoradiation [ 51 ]. Given that TMZ can presents unwanted systemic toxicity, combination strategies with the aim of reducing adverse effects and augmenting anti-tumor responses are urgently needed. Recently, in an open-label, randomized, phase III trial (NCT01149109), combined lomustine-TMZ chemotherapy prolonged overall OS survival compared with standard adjuvant therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter [ 52 ], providing new evidence that dual agent treatment may be superior to TMZ alone for GBM [ 53 ]. Despite multimodal therapies, the prognosis of GBM is still disappointing. To a certain degree, distinction of molecular subtypes within the glioma (Fig. 1 ) offer possibilities to select the proper treatment modality according to the demand of clinical practice. However, to date, the classification scheme is of limited relevance for GBM treatment due to intratumoral heterogeneity.

Immunotherapy, which harnesses the body’s immune system to against cancer, has led to important clinical advances over the past few years [ 54 , 55 , 56 ]. On the basis of therapeutic gains made in immune checkpoint blockade and CAR-modified T cells, Science awarded cancer immunotherapy its ‘Breakthrough of the Year’ in 2013 [ 56 ]. Subsequently, The Nobel Prize in Physiology or Medicine 2018 awarded discovery of cancer therapy by inhibition of negative immune regulation. These excellent findings laid the foundation for the clinical development of immunotherapy, which have dramatically improved outcomes for many people with cancer. In recent years, lots of immunotherapy drugs, from monoclonal antibody against cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1), to CAR T cell therapy, are approved by U.S. Food and Drug Administration (FDA) for cancer treatment [ 54 , 55 , 56 , 57 ]. Although no FDA-approved immunotherapies for GBM exists currently, there are several ongoing clinical trials testing in GBM patients, spurred on by advances in immuno-oncology for other tumor types [ 58 ]. Recently, treatment with immune checkpoint inhibitors demonstrated improved OS in some melanoma patients with brain metastases, suggestive of the immunotherapy as a potential treatment option for CNS tumors [ 59 , 60 ]. Despite this, a persistent challenge remain for immunotherapy in treating GBM due to the existence of redundant mechanisms of tumor-mediated immune suppression [ 61 , 62 ]. Besides, molecular heterogeneity in GBM is credited as a major mechanism of therapeutic resistance and therefore an important clinical challenge to develop effective immunotherapeutic directed against GBM [ 63 ]. In addition, adverse events (AEs) with immune-mediated mechanisms are common in patients with advanced solid organ malignancies receiving immunotherapy [ 64 ]. Based on these observations, advancements in immunotherapy for GBM is an exciting direction for the future development of treatments for GBM, but their clinical benefits remain to be seen [ 63 ].

Immune checkpoint blockade

CTLA-4 and PD-1 are negative regulators of T-cell activity that limits immune responses against cancer [ 56 ]. PD-1 binds to its ligands PD-L1, which is expressed in GBM tumors [ 66 , 67 ], and elevated expression levels was shown to correlate with poorer prognoses in some studies [ 67 ]. Ipilimumab is a human anti-CTLA-4 monoclonal antibody (mAb) that blocks CTLA-4 and its ligands (CD80/CD86) with demonstrated efficacy in metastatic melanoma [ 68 ]. Preclinical research has suggested that the combination of CTLA-4 and IL-12 blockade elicits T cell-mediated glioma rejection in a syngeneic murine model of GBM [ 69 ]. A durable survival benefit was achieved utilizing combinatorial blockade against CTLA-4, PD-L1 and indoleamine 2,3 dioxygenase 1 (IDO) in glioma-bearing mice models [ 70 ]. The nivolumab is a fully human immunoglobulin G subclass 4 monoclonal antibody inhibitor of PD-1 approved globally for the treatment of diverse cancers [ 71 ]. Growing studies have demonstrated that the PD-1/PD-L1 axis is immunologically relevant and a therapeutic window exists [ 72 , 73 , 74 ]. Taken together, these data provide preclinical evidence that combinatorial targeting immunosuppression may serves as a promising strategy for future clinical trials in patients with GBM. Since immune checkpoint blockade have revolutionized cancer treatment for several solid tumors, there exists the possibility that it can also transform the treatment of GBM. Based on these findings, an early phase I study evaluated the safety/tolerability and efficacy of nivolumab alone or in combination with ipilimumab for patients with recurrent glioblastoma [ 75 ]. In this trial, 40 patients were enrolled from 9 sites in the United States, and exploratory efficacy results indicated that ~ 20% of patients achieved stable disease ≥12 weeks, and 5 (12.5%) survived > 25 months. Additionally, nivolumab monotherapy was better tolerated than nivolumab in combination with ipilimumab and was selected for the phase III cohort (cohort 2) of (CheckMate 143, NCT02017717). It should be note that high rates of serious adverse events were observed in nivolumab with ipilimumab, thus this combination strategy is not being pursued further in the phase III stage of this trial. In this phase III trial, the efficacy and safety of nivolumab is being compared with that of bevacizumab (a monoclonal antibody to vascular endothelial growth factor) in patients with recurrent glioblastoma, the preliminary data reported at the 2017 World Federation of Neuro-Oncology Societies meeting revealed that at interim analysis of 369 patients, nivolumab monotherapy did not demonstrate a median OS benefit over bevacizumab (9.8 months with nivolumab versus 10.0 months bevacizumab) [ 45 ]. Although the study did not met the primary end point of OS, no safety concerns were reported [ 76 ]. The results also revealed that patients with methylated MGMT promoter and no baseline corticosteroid dependence may potentially derive benefit from treatment with immune checkpoint blockade [ 76 ]. In a large ongoing randomized phase II trial (CheckMate 548, NCT02667587), researchers are investigating nivolumab as an alternative to TMZ (both in combination with radiotherapy) in newly diagnosed GBM patients with methylated MGMT status. A similar ongoing phase III trial for patients with unmethylated MGMT status will also be assigned to receive nivolumab + standard radiotherapy vs. TMZ + standard radiotherapy (CheckMate 498, NCT02617589) [ 77 ]. Although the results from these two trials are unpublished at this time, the preliminary data stated by Bristol-Myers Squibb (BMS) at 2019 revealed that CheckMate 548 did not meet one of its primary endpoints and CheckMate 498 did not meet its primary endpoint of OS on final analysis [ 78 ]. Furthermore, a single-arm phase II clinical trial in which neoadjuvant nivolumab was tested in 30 patients with recurrent resectable glioblastoma observed favorable changes in the tumor immune microenvironment (NCT02550249) [ 79 ]. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later [ 79 ]. Moreover, a small randomized phase II clinical trial in this same issue [ 80 ], utilizing neoadjuvant pembrolizumab (a humanized monoclonal antibody that binds the PD-1 receptor) in patients with recurrent resectable glioblastoma described similar intratumoral effects in the immune tissue microenvironment as evidenced by [ 79 ]. The neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may provide a therapeutic window to study the immunobiology of GBM [ 80 ]. Admittedly, these two studies was a small study in which the limited sample size prevents definitive conclusions about the clinical outcome of treatment. To date, clinical trials have revealed that immune checkpoint inhibitors have limit efficacy in GBM, where < 10% of patients show long-term responses. The main reason might be that multiple genomic features are involved in the occurrence and development of GBM, which may determine the response pattern of patients with GBM to checkpoint blockade immunotherapy. To understand the molecular determinants of immunotherapeutic response in GBM, a recent study enrolled 66 patients to investigate the immune and genomic correlates of response to anti-PD-1 immunotherapy in GBM. Genomic and transcriptomic analysis revealed that PTEN mutations are associated with immunosuppressive expression signatures and resistance to immune-checkpoint inhibition, whereas tumors from responders were observed to harbour MAPK pathway alterations ( PTPN11 , BRAF ) [ 81 ]. Of note, a survival difference was seen between responders and non-responders, with a median survival of 14.3 months of responders compared to the 10.1 months of non-responsive patients. Whereas thousands of unselected patients received immune checkpoint inhibitors without evidence of significant response to date, this study showed that a sub-group of patients might benefit from this therapy, suggesting a possibility of personalized, patient-specific GBM treatment.

On the horizon: targeting “next-generation” checkpoints

Unlike the adaptive immune checkpoint PD-L1 who sends to the adaptive immune system a “don’t find me” signal, cluster of differentiation 47 (CD47) sends a “don’t eat me” signal to the innate immune system that blocks macrophages from attacking the tumor [ 88 , 89 ]. The binding of CD47 to its cognate receptor signal-regulatory protein alpha (SIRPα) on phagocytic cells leads to inhibition in the macrophage-mediated tumor cell phagocytosis. Since the recent identification of CD47/SIRPα axis as a therapeutic target for human solid tumors [ 90 , 91 , 92 ], there have been several preclinical studies examining the safety and efficacy of targeting CD47 as an immune checkpoint molecule for GBM therapy [ 93 , 94 ]. CD47 blockade by using anti-CD47 antibody was reported to stimulate phagocytosis of glioblastoma by macrophages and hence reduce tumor burden in vivo [ 95 ]. In vitro and in vivo studies demonstrated that CD47 blockade by a humanized anti-CD47 antibody (Hu5F9-G4) enhanced macrophage-mediated phagocytosis, improved survival, and reduced tumor burden in human GBM engrafted mice model [ 92 ]. In vivo study further showed that CD47 blockade could effectively reeducate microglia in the GBM tumor microenvironment to unleash the therapeutic potential of tumor cell phagocytosis [ 96 ]. Additionally, anti-CD47 immunotherapy using Hu5F9-G4 could also be combined with irradiation or TMZ chemotherapy to enhance the therapeutic efficacy of GBM treatment in vitro and in vivo [ 97 ]. Recently, a pre-clinical toxicokinetic study in non-human primates reported no adverse effects associated with Hu5F9-G4. As a matter of fact, CD47 therapeutics including Hu5F9-G4 are moving forward rapidly in the clinic, patients with acute myeloid leukemia (AML) and solid tumors are being recruited for phase I clinical trials (NCT02678338 and NCT02216409) [ 98 , 99 ]. A phase 1b study demonstrated that the combination of Hu5F9-G4 and rituximab produced durable responses in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study (NCT02953509) [ 100 ], and further investigation is ongoing in a phase II trial (NCT02953509). However, no clinical trials have been conducted in GBM to date, the development of CD47 blockade as a therapeutic target either as monotherapy or in combination with other treatments for GBM needs to be studied further.

MEDI9447 is a human monoclonal antibody that selectively binds to and inhibits the ectonucleotidase activity of CD73, and the results showed the ability of MEDI9447 in preclinical tumor models [ 107 ]. A phase I trial to test the safety, tolerability, and clinical activity of oleclumab (MEDI9447) alone and in combination with durvalumab (MEDI4736, anti-PD-L1) is currently underway (NCT02503774). Other anti-CD73 monoclonal antibodies, including BMS-986179 (NCT02754141), CPI-006 (NCT03454451) and NZV930 (NCT03549000) have been also actively tested in clinical trials [ 101 ]. Aside from mAbs, novel small-molecule inhibitors of CD73 are being developed and tested as monotherapy or in combination with other immunotherapies in preclinical and clinical trials, such as A001421 [ 94 ], AB680 (NCT04104672), CB-708, and LY3475070 (NCT04148937) [ 101 ]. A001421 have demonstrated profound effects in experimental tumor models when dosed in combination with PD-1 blockade [ 102 ]. Overall, the therapeutic efficacy of these CD73 blockade in patients with cancer is eagerly awaited. With regards to GBM, Preclinical studies showed that CD73 blockade decreases in vitro and in vivo glioblastoma growth and potentiates TMZ induced glioma cytotoxicity [ 108 ]. Further study revealed that blockade of CD73 delays glioblastoma growth by modulating the immune environment [ 109 ]. Of note, immune profiling data from multiple different human tumors and an anti-PD-1 clinical trial in patients with GBM identified CD73 as a specific immunotherapeutic target to improve outcomes for immune checkpoint therapy in glioblastoma multiforme [ 110 ]. The absence of CD73 significantly improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1 [ 110 ], suggestive of CD73 as a combinatorial target in glioblastoma. Although this reverse translational study provide some positive findings of combination immune-checkpoint blockade, it remains to be seen whether the preclinical response observed with combination immune-checkpoint blockade will translate to clinical trials in patients with GBM [ 111 ].

CAR T therapy

Genetic engineering of T cells to express CARs directed against specific antigens of tumor cells has emerged as a promising new treatment for cancer therapy [ 112 ] (Fig. 2 ). CAR are chimeric constructs containing an extracellular domain with tumor-binding moiety, typically a single-chain variable fragment (scFv), followed by a hinge of varying length and flexibility, a transmembrane (TM) region, and one or more intracellular signaling domains associated with the T-cell signaling. First-generation CARs contain the stimulatory domain of CD3ζ, whereas second-generation CARs possess a co-stimulatory domain (typically CD28 or 4-1BB) fused to CD3ζ to ensure full activation. Third-generation CARs consist of two co-stimulatory domains linked to CD3ζ to maximize signaling activation. The first co-stimulatory domain is either a CD28 or a 4-1BB domain, with the second co-stimulatory domain consisting of either a CD28, a 4-1BB or an OX40 domain. The fourth-generation CARs, combine the second-generation CAR with the addition of various genes, including cytokines and co-stimulatory ligands, to enhance the tumoricidal effect of the CAR T cells [ 113 , 114 , 115 ] (Fig. 2 ). Once the modified T cells are administered into the patient, where they can initiate cytotoxic attack on the antigen-bearing tumor cell. Since CAR recognition is either independent on MHC or effective presentation of target epitopes, CAR T therapy has the advantage of bypassing the need for MHC presentation of antigen and development of adaptive immune response [ 115 ].

The clinical potential of CAR T-cell therapy has been most convincingly shown in the field of hematological malignancies [ 116 , 117 , 118 ]. Given their extraordinary efficacy in hematological malignancies, efforts have been made to apply CAR T-cell therapies for the treatment of solid tumors including GBM [ 113 , 114 , 119 ]. Recently, several clinical CAR T cell therapies have already been tested for GBM using epidermal growth factor receptor variant III (EGFRvIII), interleukin (IL)13Rα2 (IL-13Ra2), and ephrin-A2 (Her2) as targets, with mixed but informative results [ 120 , 121 ]. Previous clinical study provide promising first-in-human clinical evidence for feasibility of intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing the foundation for further development of this IL13Rα2-specific CAR T cell therapy [ 122 ]. Building on the initial results, Brown et al. [ 123 ] report a case study in which a patient with recurrent multifocal glioblastoma received CAR T cells targeting IL-13Rα2. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding elevated levels of cytokines and immune cells in the cerebrospinal fluid [ 123 ]. The clinical response lasted for 7.5 months after the initiation of CAR T-cell therapy. While the exact cause of relapse remains to be elucidated, instances of tumor recurrence with loss and/or reduced expression of IL13Rα2 has been observed [ 122 , 123 ]. However, this study indicates that in addition to directly targeting tumor cells via IL13Rα2, the CAR T- cells induce an endogenous immune response as increased levels of non-CAR T immune cells and cytokines was observed after each infusion and the treatment was successful in initial tumors despite IL13Rα2 escape. In addition, a phase I dose-escalation study of infusing HER2-CAR-modified autologous virus-specific T cells (VSTs) (HER2-CAR VSTs) in patients with progressive glioblastoma has been conducted [ 124 ]. The data showed that infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive GBM [ 124 ].

In 2017, the results of a first-in-human clinical trial (NCT02209376) of CART-EGFRvIII in 10 patients with recurrent EGFRvIII-positive GBM were published [ 125 ]. The results demonstrated that manufacturing of CART-EGFRvIII cells from patients with recurrent GBM was safe and feasible. Although no survival benefit was observed from this small study, the authors found that CART-EGFRvIII cells infused intravenously did traffic to the brain tumor and exert antigen-directed activity [ 125 ]. In addition, lower EGFRvIII expressions and the inhibitory tumor microenvironment were also observed post-therapy [ 125 ]. Such antigen escape mechanisms may limit the durability of responses to CAR T therapy. Recently, bispecific T cell engagers (BiTEs) have been proposed as a solution against antigen escape (Fig. 2 ) [ 126 ]. By engineering EGFR-directed BiTEs, which tether T cells to tumor cells, into the EGFRvIII-CAR T cells, producing a dual-targeted platform to prevent antigen escape. EGFR-targeted BiTEs produced by CAR T cells demonstrated minimal toxicities and antitumor activity against heterogeneous tumors, highlighting a promising avenue for future developments in GBM [ 126 ]. Taken together, these preclinical findings warrant investigation in patients with GBM, which may improve the effectiveness of immunotherapy for this disease [ 127 ]. Despite some encouraging findings, the foremost limitation impeding CAR T therapy for GBM is the heterogeneity in GBM, which make it difficult to develop CAR-based strategies that can target all of the clonal populations [ 78 ]. While this approach requires further validation, modifications to mitigate tumor antigen escape and overcome antigenic heterogeneity might provide a means for effective application of CAR T therapy for GBM treatment.

Oncolytic virotherapy

The concept of virotherapy for malignancies was first demonstrated in a case report in 1912, when DePace described a woman with cervical cancer showed tumor regression after receiving an attenuated rabies virus vaccine. Since then, case studies reporting cancer remission in patients treated with naturally occurring viruses, especially in leukemias and lymphomas [ 128 , 129 , 130 ]. However, concerns of serious adverse events and the advent of chemotherapy halted early progress of oncolytic virotherapy [ 131 ]. Its potential was re-evaluated until the end of the twentieth century, supported by the evolution of viral molecular biology, as well as the development of reverse genetics system allowing for virus engineering [ 132 ]. GBM is particularly suitable for oncolytic virus (OV) therapy due to the tumor’s confinement to the brain, lack of distant metastases, and growth being surrounded mainly by post-mitotic cells, which allows for the use of viruses that require active cells cycles for replication [ 133 ].

Now, oncolytic virotherapy represents a promising form of immunotherapy for GBM treatment, which can be divided into two groups: 1) replication-competent OVs that selectively infect and replicate in cancer cells to kill tumor cells; and 2) replication-deficient viral vectors used as delivery vehicles for therapeutic genes. Currently, specific OVs have been genetically engineered to target pathogen-associated receptors present on tumor cells in order to achieve efficient and selective replication. The viral infection and amplification eventually elicit host antitumor immune responses and eliminate cancer cells. To date, over 20 oncolytic virus candidates including Herpes simplex virus Type 1 (HSV-1) [ 134 , 135 , 136 ], Adenovirus (Ad) [ 137 ], Reovirus [ 138 ], measles virus (MV) [ 139 , 140 ], Newcastle disease virus [ 141 ], and Poliovirus [ 142 ] have been tested in clinical trials to treat GBM (Table 1 ). In addition, new developments have been also made in delivery techniques for OVs to overcome limitations imposed by the BBB. Recently, Desjardins et al. reported a novel technique for convection enhanced delivery (CED) of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) [ 143 ]. PVSRIPO is a live attenuated poliovirus type 1 (Sabin) vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2 in order to restrict neurovirulence. PVSRIPO targeted GBM through CD155, a high-affinity ligand for the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains, which is broadly upregulated on malignant cells. In the phase I trial (NCT01491893), intratumoral CED of PVSRIPO in patients with recurrent GBM confirmed the absence of neurovirulent potential, and was granted breakthrough-therapy designation by FDA in May 2016. Preliminary data have revealed that the survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. On the basis of phase I findings, the phase II randomized trial (NCT02986178) of PVSRIPO alone or in combination with single-cycle lomustine in patients with recurrent GBM are underway. The therapeutic efficacy of this novel treatment modality in patients with GBM is eagerly awaited.

Since the first application of virus engineering to an oncolytic HSV in murine glioblastoma models [ 144 ], the pace of clinical activities has accelerated considerably [ 145 ], with numerous ongoing or completed trials using modified HSV constructs (Table 1 ). Trials including G207 (NCT00028158, NCT03911388 and NCT02457845), HSV-1716 (NCT02031965), M032 (NCT02062827), MVR-C252 (NCT05095441), C134 (NCT03657576) have been conducted or are ongoing in patients with GBM. G47Δ, a third-generation oncolytic HSV-1, has been tested in a Phase I–IIa trial (UMIN-CTR: UMIN000002661) for GBM patients in Japan and demonstrated the safety of G47Δ inoculated into the human brain. The subsequent investigator-initiated phase II clinical trial (UMIN-CTR: UMIN000015995) in patients with GBM has recently been completed with good results [ 146 ]. Base on the positive results from this phase II trial, G47∆ (Delytact/Teserpaturev) got conditional and time-limited approval for the treatment of malignant gliomas in Japan at June 2021. Additionally, several phase I and II trials, including (NCT02197169), (NCT01956734), (NCT03896568), (NCT01582516), and (NCT02798406) using genetically engineered oncolytic adenovirus combined with standard-of-care or immune checkpoint blockade are currently ongoing for patients with GBM (Table 1 ) and are given expectations to bring positive outcomes. Adenoviruses have also been modified to aglatimagene besadenovec (AdV-tk), an adenoviral vector containing the HSV thymidine kinase gene, followed by an antiherpetic prodrug such as valacyclovir, which functions as toxic nucleotide analogue that can kill tumor cells [ 147 ]. This approach, termed gene-mediated cytotoxic immunotherapy, was reported to be safe in newly diagnosed malignant gliomas in the phase I b clinical trial [ 148 ]. Subsequently, the phase II trial (NCT00589875) have been conducted and demonstrated notably improved survival outcomes for malignant gliomas associated with AdV-tk-based therapy [ 147 ] (Table 1 ). The clinical trials proved the safety and efficacy of OV therapy for GBM, but very few progressed to phase III trials. Previously, a phase III trial ASPECT (registered with EudraCT, number 2004–000464-28) assessed the efficacy and safety of adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir in patients with newly diagnosed resectable GBM. The ASPECT found no significant effect on OS [ 149 ]. Recently, a phase III trial (NCT02414165) of Toca511 & Toca FC was terminated for unknown reasons. Toca 511 consists of a purified retroviral replicating vector encoding a modified yeast cytosine deaminase (CD) gene. The CD gene converts the 5-flucytosine (5-FC) to the anticancer drug 5-FU in tumor cells that have been infected by the Toca 511 vector. Notably, several phase III trials for cancer immunotherapies combined with OVs have shown clinical promise for diverse cancers [ 150 ]. Oncolytic virotherapy for GBM remains promising and may impact the future of patient care. Recent studies have shown that Zika virus (ZIKV) has oncolytic activity against GSCs, suggesting that engineering of ZIKV may provide a therapeutic modality against Glioblastoma [ 151 , 152 , 153 , 154 , 155 ]. As ZIKV selectively infects and kills GSCs relative to normal neuronal cells, it may be an option to serves as a candidate for GBM therapy. Of note, despite the general safety of OV application confirmed by preclinical and clinical trials, the moderate clinical efficacy has not yet matched the preclinical promise from laboratory experiments.

Vaccine therapy

Rindopepimut (also known as CDX-110), a peptide vaccine targeting EGFRvIII has been tested in several clinical trials. In three uncontrolled phase II studies, rindopepimut vaccination in GBM patients with gross total resection and chemoradiotherapy have provided evidence of improved median survival of 24 months compared with historical controls [ 159 , 160 , 161 ]. Following these encouraging findings, an international phase III trial (NCT01480479), ACT IV was conducted to further assess the efficacy of rindopepimut in newly diagnosed patients with EGFRvIII-positive GBM. Despite the strong anti-EGFRvIII immune response generated in patients, the primary study analysis did not show a survival benefit for patients with minimal residual disease who received rindopepimut with TMZ versus those who received TMZ alone [ 162 ]. Of note, the spontaneous loss of antigen was seen in both the treatment and control arm, questioning the utility of immunotherapy targeting a single tumor antigen with heterogeneous tumor expression [ 162 ]. Recent evidence from a double-blind, randomized, phase II study (NCT01498328) in a smaller cohort of patients with recurrent EGFRvIII-positive GBM suggested favorable outcomes for rindopepimut when combined with standard bevacizumab versus bevacizumab alone [ 163 ]. Taken together, the positive results with rindopepimut in recurrent GBM in ReACT and the negative results of ACT IV in newly diagnosed GBM lend support to further clinical trials that use combination strategies such as immunotherapy with angiogenesis inhibition.

ICT107 is a six synthetic peptide stimulated DC vaccine specifically designed for GBM, which has also reached to phase III clinical trials. A phase I study demonstrated the safety of ICT-107 with a suggestion of benefit to patients who were HLA-A2 positive [ 164 ]. A phase II trial showed that ICT-107 has some therapeutic activity in HLA-A2 positive patients and led to a phase III trial (NCT02546102) in HLA-A2 + newly diagnosed patients with GBM. But this phase III trial was suspended in 2017 due to lack of funding. DCVaxL, a dendritic cell-based vaccine therapy which use whole tumor lysate to pulse patient-derived DCs. Given the promising result in preclinical models and early stage clinical trials [ 165 , 166 ], a phase III trial (NCT00045968) of DCVax-L was conducted in newly diagnosed GBM. In this trial, the overall intent-to-treat population had a median OS of 23.1 months which is superior to median OS of 15–17 months from past studies and clinical practice [ 167 ]. However, this trial was subsequently dropped for unidentified reasons. To summarize, current results from the clinical trials on vaccines for GBM are not very promising, lack of GBM-specific antigen and high heterogeneity of the tumors pose challenges to GBM vaccine therapy.

Focused ultrasound therapy

Despite incremental advances in the therapeutic approach to GBM, there has been minimal development of both new and existing drug therapies for recurrent GBM [ 6 ]. The last drug to significantly improve OS for GBM was TMZ, which was introduced 20 years ago [ 35 ]. After decades of development, bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) was granted accelerated FDA approval for recurrent GBM without the completion of a randomized Phase III trial, making bevacizumab the third FDA-approved treatment for GBM [ 170 ]. Subsequently, bevacizumab was tested in two large randomized phase III trials (NCT00884741 and NCT00943826) [ 10 , 11 ]. Despite improvement in median progression-free survival (PFS) of both trials, first-line use of bevacizumab did not improve OS in patients with glioblastoma. Consistent with this, according to a systematic analysis, the combination of bevacizumab for newly diagnosed GBM is beneficial in terms of prolonging median PFS but not OS [ 171 ]. Thus, innovative therapies are needed to ultimately improve the outcome of patients with glioblastoma. One of the major limitations of new GBM therapies in part because of inefficient drug delivery across the BBB. The BBB is formed by brain endothelial cells lining the cerebral microvasculature, presents a particular challenge for drug delivery [ 34 ]. Recently, focused ultrasound to overcome the BBB has led to the emergence of this technology as a viable new option for targeted delivery to the CNS [ 172 ]. Preclinical studies have showed that low-intensity pulsed ultrasound increased the concentrations of systemically administered drug therapies in the brain parenchyma in animal models and prolonged survival in GBM preclinical models [ 31 , 33 , 173 , 174 , 175 , 176 , 177 ].

After several decades of pre-clinical research, focused ultrasound has recently translated into clinical studies for GBM [ 178 ]. In 2016, a first-in-man, single-arm, single-center trial (NCT02253212) was initiated to evaluate the safety and feasibility of repeated pulsed ultrasound in recurrent GBM [ 34 ]. The results showed that focused ultrasound as a new technique for treating patients with GBM was safe and not burdensome [ 34 , 35 ]. More importantly, the pulsed ultrasound add-on treatment presented in this work can be extended and combined with other therapies to enhance drug penetration in patients with GBM [ 35 ]. A prospective single-arm, open-label trial was conducted to investigate serial magnetic resonance-guided focused ultrasound (MRgFUS) and adjuvant TMZ combination in patients with GBM (NCT03616860). This first-in-human proof-of-concept study showed that MRgFUS enriches the signal of circulating brain-derived biomarkers, providing data for the feasibility of a focused ultrasound framework to liquid biopsy in neuro-oncology patients [ 179 ]. Transient BBB opening in tumor using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was reported to be safe and feasible (NCT02343991) [ 180 ].

In addition, several clinical trials including (NCT04998864), (NCT04988750), and (NCT04446416) to evaluate the safety and preliminary efficacy of focused ultrasound are underway.

Conclusions and perspectives

Availability of data and materials

Not applicable.

Abbreviations

Glioblastoma

World Health Organization

Temozolomide

Glioma stem cell

Blood-brain barrier

Central nervous system

Chimeric antigen receptor T

Major Histocompatibility Complex

Antigen presenting cells

Dendritic cell

Human leukocyte antigen

Methylguanine-DNA methyl-guanine-methyltransferase

Cytotoxic-T-lymphocyte-associated protein 4

Programmed cell death protein 1

PD-1 ligand 1

U.S. Food and Drug Administration

Monoclonal antibody

Indoleamine 2,3 dioxygenase 1

Cluster of differentiation 47

Signal regulatory protein α

Acute myeloid leukemia

Adenosine triphosphate

Extracellular adenosine

Single-chain variable fragment

Transmembrane

Epidermal growth factor receptor variant III

Interleukin (IL)13Rα2

Virus-specific T

Bispecific T cell engagers

Oncolytic virus

Simplex virus Type 1

Measles virus

Convection enhanced delivery

Cytosine deaminase

5-flucytosine

Vascular endothelial growth factor

Progression-free survival

Overall survival

Magnetic resonance-guided focused ultrasound

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April 22, 2024

Genetically engineering a treatment for incurable brain tumors

Sandro Matosevic, associate professor in the Department of Industrial and Molecular Pharmaceutics in Purdue’s College of Pharmacy, leads a team of researchers that is developing a novel immunotherapy to be used against glioblastoma. (Purdue University photo/Shambhavi Borde)

Purdue researchers develop fully off-the-shelf, stem cell-derived, natural killer cells against glioblastoma

WEST LAFAYETTE, Ind. — Purdue University researchers are developing and validating a patent-pending treatment for incurable glioblastoma brain tumors. Glioblastomas are almost always lethal with a median survival time of 14 months. Traditional methods used against other cancers, like chemotherapy and immunotherapy, are often ineffective on glioblastoma.

Sandro Matosevic , associate professor in the Department of Industrial and Molecular Pharmaceutics in Purdue’s College of Pharmacy , leads a team of researchers that is developing a novel immunotherapy to be used against glioblastoma. Matosevic is also on the faculty of the Purdue Institute for Cancer Research and the Purdue Institute for Drug Discovery .

The Matosevic-led research has been published in the peer-reviewed journal Nature Communications .

The Purdue glioblastoma treatment

Matosevic said traditional cell therapies have almost exclusively been autologous, meaning taken from and returned to the same patient. Blood cells from a patient are engineered to better recognize and bind to proteins on cancer cells, then given back to the same patient to bind to and attack cancer cells. Unfortunately, these therapies have limited to no effect on glioblastoma.

“By contrast, we are developing immunotherapy based on novel, genetically engineered, fully off-the-shelf or allogeneic immune cells. Allogeneic cells are not sourced from the same patient, but rather another source,” Matosevic said. “In our study, we sourced — or rather engineered — cells from induced pluripotent stem cells. So we eliminated the need for blood and instead differentiated stem cells into immune cells, or natural killer cells, and then genetically engineered those.”

Matosevic said novel Purdue immunotherapy can be considered to have a true off-the-shelf source.

“We can envision having unlimited supplies of these stem cells ready to be engineered,” Matosevic said. “This does not require blood to be sourced. And because these are human cells, they are directly usable in human patients.”

Validation and next development steps

The research team tested its treatment by conducting animal studies with mice bearing human brain tumors, which were treated by direct injection of the newly engineered immune cells.

“Our preclinical studies showed these immune cells to be particularly remarkable in targeting and completely eliminating the growth of the tumors,” Matosevic said. “We found that we can engineer these cells at doses suitable for clinical use in humans. This is significant because one of the major hurdles to clinical translation of cell-based therapies to humans has been the poor expansion and lack of potency of cells that were sourced directly from patients. Using an off-the-shelf, fully synthetic approach breaks down significant barriers to the manufacturing of these cells.”

Matosevic said the next step to develop the glioblastoma treatment is to conduct clinical trials to treat patients with brain tumors, including those that were not successfully eliminated by surgery.

“Our ultimate goal is to bring this therapy to patients with brain tumors,” Matosevic said. “These patients urgently deserve better, and more effective, treatment options. We believe there is true potential for this therapy, and we have the motivation and capacity to bring it to the clinic.

“We are working with neurosurgical clinician collaborators to not only obtain funding, but also initiate clinical protocols,” he added. “We are also open to and always seeking new collaborations and partnerships with those who have interest in supporting our mission to translate this therapy to the clinic, where it is needed the most.”

Matosevic disclosed the innovative glioblastoma treatment to the Purdue Innovates Office of Technology Commercialization , which has applied for a patent from the U.S. Patent and Trademark Office to protect the intellectual property. Inquiries about the status of the intellectual property may be directed to Joe Kasper, assistant director of business development and licensing — life sciences, at [email protected] .

Matosevic and the research team received funding from the National Institutes of Health, the V Foundation for Cancer Research, the Purdue Institute for Cancer Research and industry partners.

About Purdue Innovates Office of Technology Commercialization

The Purdue Innovates Office of Technology Commercialization operates one of the most comprehensive technology transfer programs among leading research universities in the U.S. Services provided by this office support the economic development initiatives of Purdue University and benefit the university’s academic activities through commercializing, licensing and protecting Purdue intellectual property. In fiscal year 2023, the office reported 150 deals finalized with 203 technologies signed, 400 disclosures received and 218 issued U.S. patents. The office is managed by the Purdue Research Foundation, which received the 2019 Innovation & Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. In 2020, IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Contact [email protected] for more information.

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Purdue University is a public research institution demonstrating excellence at scale. Ranked among top 10 public universities and with two colleges in the top four in the United States, Purdue discovers and disseminates knowledge with a quality and at a scale second to none. More than 105,000 students study at Purdue across modalities and locations, including nearly 50,000 in person on the West Lafayette campus. Committed to affordability and accessibility, Purdue’s main campus has frozen tuition 13 years in a row. See how Purdue never stops in the persistent pursuit of the next giant leap — including its first comprehensive urban campus in Indianapolis, the new Mitchell E. Daniels, Jr. School of Business, and Purdue Computes — at https://www.purdue.edu/president/strategic-initiatives .

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Chemo for glioblastoma enhanced by tapping into cell’s daily rhythms

Study reveals mechanism for why treatment appears to work better in the morning

Glioblastoma is an aggressive brain cancer that has no cure. A recent chart study of patients with glioblastoma found that taking chemotherapy in the morning was associated with a three- to six-month increase in median survival .

Now a study from Washington University in St. Louis reports that glioblastoma cells have built-in circadian rhythms that create better times of day for treatment.

Biologists and clinicians recorded daily rhythms in “clock gene” expression from a variety of cultured human and mouse glioblastoma cell lines and isolates. These rhythms aligned with daily activity of a DNA repair enzyme known as MGMT. The scientists then conducted tests and found that tumor cells were more likely to die when chemotherapy was administered at the time of day — the morning — when tumor cells had the least MGMT activity.

Repeating their efforts in mice with glioblastoma, the scientists found that morning administration of chemotherapy decreased tumor size and increased body weight compared with evening drug delivery.

The study was published in the Journal of Neuro-Oncology .

“There might be an avenue for better treating this disease with a drug at the times of day when the cells are more susceptible,” said Maria F. Gonzalez-Aponte, a graduate student in biology in Arts & Sciences at Washington University, who is a first author of the new study. “We found that delivering chemotherapy with temozolomide (TMZ) in the subjective morning can significantly decrease tumor growth and improve disease outcomes for human and mouse models of glioblastoma.”

“Because TMZ is taken orally at home, translation of these findings to patients is relatively simple,” said Erik D. Herzog , PhD, the Viktor Hamburger Distinguished Professor and a professor of biology in Arts & Sciences, corresponding author of the new study.

“We will need additional clinical trials to verify our laboratory findings, but evidence so far suggests that the standard-of-care treatment for glioblastoma could be improved simply by asking patients to take the approved drug in the morning,” Herzog said.

While largely understudied for TMZ and glioblastoma, the practice of considering time of day in treating disease has been shown to improve outcomes in several cancers, including acute lymphoblastic leukemia, colorectal and ovarian and other gynecological cancers, study authors noted. Joshua B. Rubin , MD, PhD, a professor of pediatrics and of neuroscience at the School of Medicine, is a longtime collaborator with the Herzog laboratory and a co-author on the paper. Gary J. Patti , PhD, a professor of chemistry in Arts & Sciences and of medicine at the School of Medicine, and staff scientist Kevin Cho, PhD, in chemistry are also co-authors.

Findings from this study have implications for both treatment and diagnosis of glioblastoma.

In general, glioblastoma patients who are diagnosed with what is called MGMT methylated tumors tend to respond better to chemotherapy with TMZ.

But this study found that MGMT methylation levels rise and fall based on the circadian time of the tumor. As a result, doctors should control for the time of day when the biopsy of a tumor is taken to properly compare results and improve diagnoses, study authors said.

“Despite extensive research over the past 20 years, the median survival for glioblastoma patients post-treatment remains at about 15 months, a grim statistic,” Herzog said. “Incorporating chronotherapy, or timed delivery of drugs, could help improve things.”

Herzog, Patti and Rubin are research members of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Funding: This work was supported by National Institutes of Health (NIH) grants NINDS R21NS120003 and the Washington University Siteman Cancer Center. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Gonzalez-Aponte, M.F., Damato, A.R., Trebucq, L.L. et al. Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma. J Neurooncol (2024). https://doi.org/10.1007/s11060-023-04535-9

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‘Fight or flight’ – unless internal clocks are disrupted, study in mice shows

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Vulnerability in Brain Tumors May Open Door to New Treatments

September 26, 2022 , by Edward Winstead

A fluorescence micrograph of glioma organoids.

To explore potential treatments for gliomas, researchers developed models called organoids (pictured) using tumor samples donated by people with these lethal brain cancers.

Two new studies have uncovered a vulnerability in different forms of brain tumors that may make the cancers susceptible to the same treatments. The brain tumors are gliomas, which are among the most lethal cancers.

One study focused on diffuse midline gliomas, which occur most often in children. The other study focused on gliomas with mutations in the IDH1 or IDH2 genes , which tend to occur in adults.

Both investigations led to a similar insight: Some gliomas become dependent for their survival on one of the ways that cells produce chemicals called pyrimidine nucleotides, which are components of DNA .

The dependence of certain glioma cells on this process, called de novo pyrimidine nucleotide synthesis, creates a vulnerability. And the new research suggests that a drug may be able to exploit this vulnerability for the benefit of patients with gliomas.

In both studies, a drug called BAY 2402234 penetrated the brains of mice with gliomas and shrank their tumors, though by different mechanisms. Results from the NCI-supported studies were published in Cancer Cell on August 18.

Based on the findings, both teams of investigators are planning clinical trials to test the drug in people with diffuse midline glioma or IDH -mutant glioma.

“This drug prevents the formation of one of the building blocks of DNA, reducing the ability of cancer cells to divide or repair themselves and leading to cell death,” said Mioara Larion, Ph.D., of NCI’s Center for Cancer Research , who studies brain tumors but had no role in the new studies.

The finding that “two vastly different brain tumors share a common vulnerability was unexpected and very interesting,” Dr. Larion continued. “We and others are excited about the possibility of using inhibitors that target certain metabolic pathways to treat patients.”

Desperate need for new treatments

Gliomas are the most common brain tumor among adults. The cancer is usually fatal, and no new drugs have been approved for the disease over the past decade.

“There is a desperate need for new treatments for glioma brain tumors,” said Diana Shi, M.D., of the Dana-Farber Cancer Institute, and a member of the team that conducted the study of gliomas with IDH mutations.

Dr. Shi and her colleagues identified BAY 2402234 while screening hundreds of compounds for their ability to slow the growth of IDH -mutant glioma cells. The drug, which has been tested in people with leukemia, blocks the activity of an enzyme called DHODH, which is involved in pyrimidine synthesis.

In experiments with mouse models, the drug inhibited the growth of IDH -mutant gliomas but not gliomas without the mutations .

In glioma cells, IDH mutations can cause DNA damage when there is an imbalance in the level of nucleotides. These imbalances are caused by blocking pyrimidine synthesis, the researchers found.

They also observed that genes involved in sensing and repairing DNA damage were less active in IDH -mutant gliomas than in gliomas without these mutations.

“We believe that patients with IDH -mutant gliomas may benefit from treatments that target ... DHODH,” said Samuel McBrayer, Ph.D., of the Children’s Medical Center Research Institute at UT Southwestern, who co-led the study with William G. Kaelin, Jr., M.D., of Dana-Farber.

As a next step, the researchers are working to reach an agreement with the developers of BAY 2402234, the Broad Institute and Bayer Pharmaceuticals, to launch a clinical trial of the drug in people with certain types of glioma.

The trial will be sponsored by NCI’s Glioblastoma Therapeutics Network (see box) and will focus on a type of glioma called grade 4 IDH -mutant astrocytoma .

Developing new models of gliomas

A challenge in developing treatments for gliomas has been the limited number of models for assessing how a drug may affect a brain tumor.

“We don’t have a great way to evaluate new drugs before they are tested in patients who have gliomas, and this has been a real bottleneck in the research,” said Kalil Abdullah, M.D., a neurosurgeon who specializes in treating brain tumors at the University of Pittsburgh’s Hillman Cancer Center.

To address this challenge, his laboratory has developed models called surgically explanted organoids, which are tiny 3-dimensional representations of a patient’s tumor. These models are derived from tissue samples collected during brain surgery, and they retain many of the biological characteristics of the original tumor .

In the new study, BAY 2402234 preferentially killed organoids created from IDH -mutant gliomas relative to organoids created from gliomas that lacked the mutations.

“As far as we know, this was the first study to use organoids developed from patients with lower-grade gliomas to evaluate a new drug,” said Dr. Abdullah. “And the results were very promising.”

Urgent need for progress against gliomas in children

As with gliomas in adults, there has been little progress in developing new treatments for gliomas that occur in children. The category of diffuse midline gliomas includes aggressive tumors known as diffuse intrinsic pontine gliomas, which occur most often in children and are almost uniformly fatal.

“There have not been advances of any substance for the treatment of diffuse midline gliomas in many, many decades,” said Daphne Haas-Kogan, M.D., who chairs the Department of Radiation Oncology at Dana-Farber and led the new study of these gliomas.

“The only intervention that works to alleviate the patient’s symptoms is radiation,” she continued. “But radiation is not curative, and therefore every patient with this disease dies.”

To identify new treatments for diffuse midline gliomas, Dr. Haas-Kogan and her colleagues conducted a CRISPR screen, which can reveal genes that are needed for the survival of certain cells. For some diffuse midline gliomas, the de novo pyrimidine nucleotide synthesis pathway appears to be essential , the researchers found. This dependency may arise because an alternate pathway used to produce pyrimidines stops working as it should, they believe.

“We’d like to develop a better understanding of this mechanism,” Dr. Haas-Kogan said. “The work could reveal additional vulnerabilities in these tumors that might point to potential therapies.”

When the researchers tested the drug BAY 2402234 in mouse models of diffuse midline gliomas, it shrank tumors. But the tumors eventually started growing back, and the mice died of the disease.

“The drug prolonged survival in the mice, but it’s not a cure,” said Sharmistha Pal, Ph.D., of Dana-Farber and a coauthor of the study. She noted that many cancers develop resistance to individual therapies, and the researchers are exploring strategies for overcoming drug resistance .

The researchers are planning to test BAY 2402234 in patients with diffuse midline gliomas through the Pacific Pediatric Neuro-Oncology Consortium. The group, which includes more than 20 hospitals around the world, has trials for patients with diffuse midline gliomas that allow for new agents to be added as they are discovered.

Building a strong scientific collaboration

The Cancer Cell studies of gliomas highlight the value of collaboration among researchers who study different types of cancer, noted Amanda Haddock, president of Dragon Master Foundation, a nonprofit dedicated to accelerating cancer research, who had no role in the glioma studies.

These studies began as independent investigations. But several years ago, the research teams began to share information after Drs. Haas-Kogan and Kaelin had a serendipitous conversation at a scientific meeting on gliomas.

After a day of presentations at Cold Spring Harbor Laboratory, the Dana-Farber colleagues met before dinner. As they chatted, each investigator shared the outlines of their glioma research, revealing the existence of parallel studies.

“At that point, we joined forces,” said Dr. Haas-Kogan, who noted that the collaboration accelerated her team’s work. For one thing, Drs. Kaelin and McBrayer had already identified BAY 2402234 as a potential treatment for IDH -mutant gliomas, and Dr. Haas-Kogan was not aware of the drug.

Just as important, Dr. McBrayer’s team had expertise on designing studies of metabolic pathways and interpreting the results. “They shared this knowledge with us over many Zoom calls,” said Dr. Haas-Kogan.

Likewise, Dr. McBrayer said his team benefited from collecting “corroborating evidence from two subsets of brain tumors.” The hope now is that people with gliomas will one day benefit as well.

“Fortunately, these researchers discovered each other and could complement each other’s work,” said Haddock. “This is exactly the kind of collaboration that is in the best interest of the patients, and we need to encourage and reward this type of work.”

Making progress in treating glioblastoma

Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance

Affiliations.

1 Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA.
2 Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
3 Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
4 Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA.
5 Department of Neuropathology, Institute of Pathology, Technical University of Munich, Munich, Bayern 81675, Germany.
6 Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 34302977
PMCID: PMC8384724
DOI: 10.1016/j.phrs.2021.105780

Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.

Keywords: Carmustine (PubChem CID: 2578); Cediranib (PubChem CID: 9933475); Chemotherapy; Erlotinib (PubChem CID: 176870); Gefitinib (PubChem CID: 123631); Glioblastoma; Immunotherapy; Irinotecan (PubChem CID: 60838); Lomustine (PubChem CID: 3950); Nanotherapy; Niraparib (PubChem CID: 24958200); Olaparib (PubChem CID: 23725625); Radiotherapy; Targeted therapy; Temozolomide (PubChem CID: 5394); Veliparib (PubChem CID: 11960529).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Systematic Review
Antineoplastic Agents / therapeutic use*
Brain Neoplasms / drug therapy*
Drug Resistance, Neoplasm
Glioblastoma / drug therapy*
Antineoplastic Agents

Grants and funding

P30 CA124435/CA/NCI NIH HHS/United States
R01 HD103638/HD/NICHD NIH HHS/United States
T32 CA009695/CA/NCI NIH HHS/United States

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News & Publications

A potential new target to fight glioblastoma.

Recent research at Johns Hopkins and Tel Aviv University sheds light on how glioblastoma tumors may avoid roadblocks that the immune system sets up to prevent spread from the primary site. The findings, published recently in Nature Communications , could offer an entirely new way to fight this most common and lethal type of primary brain tumor.

Glioblastomas are characterized by their highly invasive nature, explains study co-author Henry Brem , director of the Johns Hopkins Department of Neurosurgery . Because tumor cells disperse throughout the brain, existing treatments — including combinations of surgery, chemotherapy and radiation — have been unable to eradicate these cancers in patients, causing the disease to recur again and again.

“We have made incredible progress, doubling median survival up to 20 months over the last decade,” Brem says. “But we are still very far from where we want to be with survival and being able to treat with the right therapy.”

The new research offers a window into why glioblastomas are so difficult to treat, and the findings could lead to new therapies that hijack the mechanism that makes them so pernicious. The study focused on the interaction between glioblastoma cells and microglia, which are cells that serve as the brain’s immune system.

When the researchers placed glioblastoma and microglia cells together in a petri dish, they found that both cells began to oversecrete a protein called P-selectin (SELP), a cell adhesion molecule that has been linked to immune function and the spread and metastasis of some cancers. Further investigation using fresh frozen paraffin-embedded tumor samples from patients with glioblastoma further emphasized that this protein could play a key role in the disease: Tumors from patients who did not survive long had more SELP than those from long-surviving patients, suggesting that more SELP was associated with worse outcomes.

To determine the role of SELP in glioblastoma, the researchers blocked SELP function in cultured tumor cells with a commercially available SELP inhibitor — a neutralizing anti-SELP antibody. These cells exhibited significantly less proliferation and migration than cells with normal SELP function. The cells with blocked SELP also produced more inflammatory molecules and proteins that recruit T-cells compared with cells with normal SELP, suggesting that SELP is necessary to launch an effective immune attack. When the researchers blocked SELP in glioblastoma animal models, their tumors showed delayed growth and improved immune cell infiltration, and the animals survived significantly longer than those with functioning SELP.

Ultimately, says study co-author Thomas Hyde , a Johns Hopkins neuropathologist who co-directs the Lieber Institute for Brain Development’s human brain repository — where human tissue was derived for this study — SELP could be a new target for treating glioblastoma.

For glioblastoma, a new clinical trial fosters innovation and hope

by Anna Megdell, University of Michigan

A new clinical trial from a team at the University of Michigan Rogel Cancer Center uses innovative basic science research methods to offer hope and a new treatment to glioblastoma patients. A collaborative team of Rogel physicians, led by Daniel Wahl, M.D., Ph.D., hopes that grounding their trial in rigorous and innovative biology from the very beginning will help this approach succeed where so many other potential glioblastoma treatments have failed.

Exploring these types of advances in glioblastoma treatment is urgent. The aggressive brain tumor is largely resistant to current treatment, almost always recurs, and comes with a grim prognosis. Further, many new therapies fail to cross the blood-brain barrier, making drugs that would otherwise be effective often unable to reach the cancer cells. This reality of glioblastoma, and the lack of new effective treatments in the last 15 years, motivates Wahl and his team.

The clinical trial, which began in August 2020, has its foundation in Wahl's medical training and Ph.D. studying metabolism, all performed at U-M. While taking care of glioblastoma patients during a residency in radiation oncology, Wahl saw firsthand the consequences of these aggressive treatment-resistant brain tumors . Most glioblastoma patients live less than a year-and-a-half from diagnosis, and fewer than 5% live five or more years.

"Radiation is one of the few treatments that work for glioblastoma, but it doesn't work well enough," Wahl explained. "Because of how important metabolism is for so many biologic functions, and how different metabolism is in cancer cells compared to the normal body, I thought metabolic pathways might be partly to blame for this resistance."

First, Wahl needed to understand the relationship between metabolites —small nutrients like sugars, amino acids, and fats—and tumor treatment response. Measuring a variety of tumor models, Wahl's team searched for a correlation between the high levels of different metabolites and the tumor models with the highest radiation resistance. Toward the end of his post-doctoral fellowship, he and his team found what they were looking for. "Purines, the metabolites that are the building blocks of DNA, were really, really high in the brain tumors that were most resistant to radiation."

But how important was this finding? When more purines were added into a glioblastoma cell, did the cells become more resistant to radiation? If purine levels were decreased, did the tumor become more sensitive to radiation? The answers were a resounding yes.

"Not only were high purines associated with treatment resistance, they also caused treatment resistance," said Wahl.

With this, Wahl set out to see if this causal relationship between high purine levels and glioblastoma radiation resistance could be leveraged to make clinical treatments more effective. He looked for FDA-approved drugs on the market that altered purine levels and found mycophenolate mofetil, a purine blocker used to prevent organ rejection in transplant patients. Moreover, mycophenolate eliminated guanosine triphosphate, the main purine responsible for radiation resistance.

In the lab, Wahl's team explored using mycophenolate mofetil on glioblastoma tumors grown in mouse models. To their delight, the drug made radiation work better. "When we saw those lab results, we knew we had to write a clinical trial."

To do so, Wahl partnered with Yoshie Umemura, M.D., a neuro-oncologist at the Rogel Cancer Center and expert in clinical trial writing and design, and Wajd Al-Holou, M.D., a neurosurgeon specializing in oncology. Together they have developed the Michigan Medicine Multidisciplinary Brain Tumor Clinic, the first multi-disciplinary treatment-focused brain tumor clinic at the University of Michigan. In this clinic, Wahl, Umemura and Al-Holou see patients and determine treatment plans together. It was this clinic that "allowed us to develop ideas as a team to tackle this difficult problem," said Al-Holou.

The clinical trial started in August 2020 for patients with recurrent glioblastoma tumors who'd previously received radiation but whose tumors had returned. In the trial, these patients receive mycophenolate mofetil alongside additional radiation treatment. To date, the team has treated about a dozen patients, and has since expanded the bounds of the trial to include patients with new glioblastoma diagnoses, incorporating updated laboratory results showing that mycophenolate also made chemotherapy more effective. This arm of the trial started in late 2021 and five patients have been treated at the time of publication.

"It's all still ongoing and too early to tell, but so far, treatment has been really safe with no serious toxicities," said Wahl.

For Umemura, the strength of this trial lies in the symbiotic relationship between clinical care and lab research, and the collaboration amongst researchers.

"This trial has a rigorous basic science backbone to support the addition of an inexpensive drug that is widely available. If we can prove there is an added benefit in treatment efficacy—which would be the next step after we can show it's safe— then this treatment regimen is likely readily incorporated into clinical care without challenges in cost or accessibility for patients."

Barrier crossing

As the team gets further into the clinical trial, understanding how well the drug reaches the tumor stays a focus. Part of figuring out the efficacy of the purine blocker relies on finding a safe dosage strong enough to traverse the blood-brain barrier , which often renders glioblastoma treatments ineffective, and determining whether the drug has the expected effect. As Al-Holou describes, most clinical trials fail to understand the impact this barrier plays. Because of an inability to determine if drugs cross this barrier, researchers often remain puzzled at the last phase of a trial, uncertain about what, and when, things went wrong.

"The last major advancement in glioblastoma treatment was more than 15 years ago," Al-Holou noted. "Our team is not only bringing a new drug that hasn't been tried before, but we're also making sure it gets into the brain and does what it's supposed to do from the very beginning."

To do this, glioblastoma patients needing surgery receive mycophenolate before their procedure and then researchers freeze tumor tissue in the operating room. Later, Wahl and his laboratory team analyze this tumor tissue to determine how much mycophenolate reached the tumor and how well purine metabolism was blocked.

Wahl, Umemura and Al-Holou are also working to determine which glioblastoma patients are most likely to benefit from mycophenolate treatment. The team hypothesizes that patients whose tumors have high activity of purine metabolism, not just high purine levels, might benefit most from these drugs. Wahl likens this to traffic.

"Imagine a freeway full of speeding cars. Blocking a road like this would be disastrous. Now imagine a second freeway also full of cars, but they're not moving: like a traffic jam. Though the traffic jam is also full of cars, putting down a roadblock wouldn't matter much. We think that tumors making lots of purines are like that fast freeway and will be most affected by mycophenolate, which is the roadblock."

But as the research progressed, a problem emerged.

Standard analysis of tumor tissue just reveals how many purines are present (the number of cars). It doesn't tell how active purine synthesis is (how fast the cars are moving). So Wahl, Al-Holou and others teamed up to use a new method called Stable Isotope Tracing to measure how quickly purines are being made in patient tumors.

"We think we might be the very first people in the world to measure this metabolic pathway activity in a patient's brain tumor," said Wahl. "And now that we can measure it, it could help us figure out which patients will benefit the most from drugs that block it."

Staying the course

The trial still has a long way to go, and Wahl and his team hope to figure out a safe dose of mycophenolate that can be used alongside radiation and chemotherapy, and to get a hint of whether that dose might improve patient outcomes, in the next few years. Then, they'll be able to decide if the trial is ready to move to a randomized clinical trial, which would require hundreds of patients from across the country. The team is currently designing this phase with the Alliance for Clinical Oncology, a national cooperative group.

"It's not guaranteed that it will happen, but we're very optimistic," Wahl said.

But for these researchers, the use of innovative methods already garners hope for patients facing dire circumstances.

"It's exciting to be giving something new to patients who really, really need it. To be able to sit with a patient and say, "We've been working hard to figure things out, and we now have something we can try," is really meaningful and motivating."

This phase of the research Wahl's been pursuing for years is also personally gratifying.

"Right now, I get to use all my training, from thinking about atoms, molecules, mass spectrometry and metabolism, to studying cells and animal tumor models in the lab, to caring for patients hands-on and talking to them about a clinical trial. Each of these skills, and the skill and dedication of the great people I get to work with, like Dr. Umemura and Dr. Al-Holou, are required to create change for patients."

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Promising Treatment for Deadly Brain Cancer

Andrew b. lassman, md.

A clinical trial has found that selinexor, the first of a new class of anti-cancer drugs, was able to shrink tumors in almost a third of patients with recurrent glioblastoma, an aggressive brain cancer.

“Glioblastoma is an incurable brain cancer that needs new therapeutic approaches. Considering that few treatments have any measurable effect on recurrent glioblastomas, the results are encouraging,” says the study’s leader, Andrew B. Lassman , MD, the John Harris Associate Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons and chief of the Neuro-Oncology Division at Columbia University Irving Medical Center / NewYork-Presbyterian .

“The drug induces a response in certain patients, and several trial patients stayed on selinexor for more than 12 months, including one for over 42 months,” adds Dr. Lassman, who also is associate director for clinical trials at the Herbert Irving Comprehensive Cancer Center .

The study was published January 10, 2022 in Clinical Cancer Research .

Glioblastomas are typically treated with a combination of surgery, radiation therapy, chemotherapy, and sometimes an electrical device, but the average survival time is just 12 to 18 months.

Selinexor, an oral medication, inhibits, exportin-1 (XPO-1), a major exporter of proteins from the nucleus to cytoplasm that is overexpressed in many cancers, including glioblastoma. Exportin inhibition results in retention of various tumor suppressor proteins in the nucleus, inducing reactivation of tumor suppressor function as well as other antineoplastic effects. Selinexor was approved by the FDA for the treatment of refractory multiple myeloma and relapsed/refractory diffuse large B-cell lymphoma and had pre-clinical activity against glioblastoma models.

Dr. Lassman led the international phase 2 trial to identify the optimal dosing schedule and evaluate the safety and efficacy of selinexor in adults with recurrent glioblastomas whose cancer had progressed following initial treatment.

Reduction in tumor size was observed in 28% of patients, and a tolerable dose was identified for future human trials already ongoing at Columbia and collaborating sites.

The most common treatment-related side effects were fatigue (61%), nausea (59%), decreased appetite (43%), and low platelet counts (43%). All these side effects were manageable with supportive care and dose modification.

There were also a robust set of molecular correlative analyses performed, including an effort led by Andrea Califano , Dr., chair of the Department of Systems Biology at Columbia University Vagelos College of Physicians and Surgeons, to identify a molecular signature in baseline tumor tissue that is predictive of patient benefit from selinexor. Drs. Lassman, Califano, and others are planning a subsequent study to validate this signature in a subsequent trial of patients with newly diagnosed glioblastoma.

“Taken together, we believe that our findings show that selinexor is an active drug in some patients with glioblastoma and is worthy of further study,” says Dr. Lassman.

An ongoing trial available at Columbia is evaluating the safety and efficacy of selinexor in combination with other therapies for patients with newly diagnosed or recurrent glioblastoma.

More information

The paper is titled “A Phase 2 Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.”

All authors: Andrew Lassman (Columbia), Patrick Y. Wen (Dana Farber Cancer Institute), Martin van den Bent (Erasmus MC Cancer Institute), Scott R. Plotkin (Massachusetts General Hospital), Annemiek M. E. Walenkamp (University Medical Center Groningen), Adam L. Green (University of Colorado and Children’s Hospital Colorado), Kai Li (Karyopharm Therapeutics), Christopher J. Walker (Karyopharm Therapeutics), Hua Chang (Karyopharm Therapeutics), Sharon Tamir (Karyopharm Therapeutics), Leah Henegar (Karyopharm Therapeutics), Yao Shen (DarwinHealth Inc), Mariano J. Alvarez (DarwinHealth Inc and Columbia), Andrea Califano (Columbia), Yosef Landesman (Karyopharm Therapeutics), Michael G. Kauffman (Karyopharm Therapeutics), Sharon Shacham (Karyopharm Therapeutics), and Morten Mau-Soerensen (Copenhagen University Hospital, Denmark).

The study was funded by Karyopharm Therapeutics and the investigators were also supported by the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian, and the National Institutes of Health (U01 CA217858, P30CA013696, UG1CA189960, S10 OD012351, and S10 OD021764.)

Potential conflicts of interest are listed in the online version of the paper.

Related Information

Meet our team.

Chief, Division of Neuro-Oncology
Associate Director for Clinical Trials, Herbert Irving Comprehensive Cancer Center
Associate Dean of Clinical Research Compliance, Vagelos College of Physicians & Surgeons, Columbia University
Scientific Director, Network Capacity Resource, Irving Institute for Clinical & Translational Research

Andrea Califano, Dr

Chair, Department of Systems Biology
Director, JP Sulzberger Columbia Genome Center
Co-Leader, Precision Oncology and Systems Biology Program, Herbert Irving Comprehensive Cancer Center

Clinical Trials

Glioblastoma.

Displaying 38 studies

The purpose of this study is to evaluate the safety and effectiveness of using Exablate Model 4000 Type-2.0/2.1 in adults with Glioblastoma brain tumors to increase temporarily the permeability of the blood brain barrier, allowing increased passage of circulating free DNA (cfDNA) for sampling and analysis.

The purpose of the study is to compare the efficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent glioblastoma (a type of brain cancer, also known as GBM), and to evaluate the safety and tolerability of nivolumab administered alone or in combination with ipilimumab in patients with different lines of GBM therapy.

This study aims to evaluate the safety of preoperative radiosurgery in the treatment of patients with biopsy-proven high grade glioma prior to conventional therapy. Safety is defined as any acute grade 3 (CTCAE v5.0) or greater unplanned adverse event from the time of enrollment until 4 weeks following postoperative radiotherapy.

The purpose of this study is to test the effectiveness and safety of Optune® given concomitantly with radiation therapy (RT) and temozolomide (TMZ) in newly diagnosed GBM patients, compared to radiation therapy and temozolomide alone. In both arms, Optune® and maintenance temozolomide are continued following radiation therapy.

This research study is studying several investigational drugs as a possible treatment for Glioblastoma (GBM). The drugs involved in this study are : - Abemaciclib - Temozolomide (temodar) - Neratinib - CC115

This randomized phase II/III trial studies how well temozolomide and veliparib work and compare them to temozolomide alone in treating patients with newly diagnosed glioblastoma multiforme. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more effective with or without veliparib in treating glioblastoma multiforme.

The purpose of this study is to assess whether there is superiority of overall survival (OS) when enzastaurin rather than placebo is added to the regimen of temozolomide with radiation therapy followed by temozolomide for the treatment of patients with newly diagnosed glioblastoma in Denovo Genomic Marker 1 (DGM1) biomarker-positive patients.

The purpose of this study is to utilize fresh tumor tissue to aid the development of future therapies for brain cancer.

The purpose of this study is to examine the pharmacological effects of the compound BI 907828 on patient tumors at an early stage of drug development.

The purpose of this study is to assess progression-free survival (PFS) and overall survival (OS) in newly diagnosed Glioblastoma multiforme (GBM) participants treated with IGV-001 as compared with placebo.

The purpose of this study is to combine MRI images with histologic and genetic analysis of cancer (from blood and tissue samples) to improve the overall accuracy of diagnosis and effectiveness of cancer treatment.

This randomized phase II trial studies how well dose-escalated photon intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy works compared with standard-dose radiation therapy when given with temozolomide in patients with newly diagnosed glioblastoma. Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as temozolomide, may make tumor cells more sensitive to radiation therapy. It is not yet known whether dose-escalated photon IMRT ...

The purpose of this study is to evaluate the safety and tolerability of marizomib in combination with Temozolomide-based radiochemotherapy versus standard Temozolomide-based radiochemotherapy alone in newly diagnosed glioblastoma patients.

The purpose of this study is to demonstrate non-inferior 12-month overall survival of patients with GlioblastomA (GBM) treated with dose escalated hypofractionated radiotherapy compared to standard of care. Also, to demonstrate the safety and favorable quality of life via physician-reported G3+ toxicitycompare if SBRT is non-inferior to standard of care on the proportion of overall survival of patients with glioblastoma 12 months after randomization.

The purpose of this study is to create a new Magnetic resonance imaging (MRI) technique with true contrast to the background reference points in functional MR images of individual patients. Functional MRI has been widely used in staging, grading and treatment response monitoring of glioblastoma. MRI has great soft tissue and tumor tissue contrast and can assist in outlining the target. It has proven able to offer functional information such as cell density, permeability of the micro-blood vessels, and the oxygen level of the tumor.

This study aims to evaluate the safety of local delivery of AMSCs for recurrent GBM by noting the incidence of adverse events, as well as radiological and clinical progression.

To assess the preliminary efficacy of local delivery of AMSCs for recurrent GBM by comparing the clinical, survival, progression, and radiographic outcomes from patients enrolled in our study to historical controls from our institution.

The purpose of this study is to evaluate the side effects of vaccine therapy in treating patients with glioblastoma that has come back. Vaccines made from a person's white blood cells mixed with tumor proteins from another person's glioblastoma tumors may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy may work better in treating patients with glioblastoma.

This phase II trial studies how well dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) works in measuring relative cerebral blood volume (rCBV) for early response to bevacizumab in patients with glioblastoma that has come back. DSC-MRI may help evaluate changes in the blood vessels within the cancer to determine a patient?s response to treatment.

This randomized phase II trial studies how well giving vaccine therapy with or without bevacizumab works in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. Vaccines consisting of heat shock protein-peptide complexes made from a person's own tumor tissue may help the body build an effective immune response to kill tumor cells that may remain after surgery. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them. It is not yet known whether giving vaccine ...

The primary objective of this study is to assess the effect of berubicin compared with lomustine on overall survival (OS) in adult patients with Glioblastoma Multiforme (GBM) (WHO Grade IV) that has recurred after standard initial therapy.

The purpose of this study is to determine the response rate to the combination of pembrolizumab and NT-I7 in patients with recurrent glioblastoma.

This is an adaptive design, randomized controlled, Phase 3 clinical trial in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS), previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now has progressive disease during or after bevacizumab. A total of up to 180 eligible patients with recurrent/progressive GBM or GS will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days ...

The primary purposes of this study are to identify experimental therapies that improve OS for GBM patients in the Screening stage (Stage 1), determining if predefined patient subtypes or associated biomarkers uniquely benefit from the treatment and to confirm identified effective experimental therapies and associated biomarker signatures in an expansion stage (Stage 2) designed to support a new drug application.

The purpose of this study is to assess the safety and technical feasibility of TheraSphere GBM in patients with recurrent glioblastoma (GBM).

This partially randomized phase I/II trial studies the side effects and the best dose of anti-endoglin monoclonal antibody TRC105 when given together with bevacizumab and to see how well they work in treating patients with glioblastoma multiforme that has come back. Monoclonal antibodies, such as anti-endoglin monoclonal antibody TRC105 and bevacizumab, may find tumor cells and help kill them. Giving anti-endoglin monoclonal antibody TRC105 together with bevacizumab may be an effective treatment for glioblastoma multiforme.

This phase II trial studies the side effects and how well pembrolizumab works in combination with standard therapy in treating patients with glioblastoma. Drugs used in the chemotherapy, such as pembrolizumab and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving pembrolizumab and standard therapy comprising of temozolomide and radiation therapy may kill tumor cells.

The purpose of this study is to assess the safety and effectiveness of combined Toca 511 and Toca FC, versus a standard of care single agent chemotherapy, for patients who are having surgery to remove a first or second recurrence of glioblastoma or anaplastic astrocytoma.

The purpose of this study is to evaluate the effect of immunotherapy drugs (ipilimumab and nivolumab) in treating patients with glioblastoma that has come back (recurrent) and carries a high number of mutations. Cancer is caused by changes (mutations) to genes that control the way cells function. Tumors with high number of mutations may respond well to immunotherapy. Immunotherapy with monoclonal antibodies such as ipilimumab and nivolumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma ...

This is a peripheral blood Collection Protocol to study the T-cell immune responses of patients with malignancies displaying one of three different patterns of antigen expression: (1) Cohort 1 focuses on cancers displaying a high (80-90%) frequency of MUC1 expression and variably high (unreported to 50%) HER2/neu (“HER2”) expression; (2) Cohort 2 focuses on primary or secondary myelofibrosis (MF) displaying mutated calreticulin (muCALR); (3) Cohort 3 focuses on glioblastoma multiforme (GBM) which often displays the cytomegalovirus tegument protein CMVpp65. Cohort 1 includes blood collections for in vitro studies which are a component of NIH-funded Project 3 within the Mayo Clinic ...

The purpose of this study is to identify common genetic variants contributing to the risk of glioma. Evaluate gene-gene and gene-environmental interactions with strong biologic relevance to identify gene-gene and gene-environment interactions for glioma risk.

The objectives of this study are to determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of NMS-03305293 in combination with temozolomide (TMZ) in patients with diffuse gliomas at first relapse (Phase I), and to determine the antitumor effectiveness of the combination of NMS-03305293 and TMZ in patients with isocitrate dehydrogenase (IDH) wild type glioblastoma at first relapse as measured by the 6-month Progression Free Survival (PFS) rate (Phase II).

The purpose of this study is to evaluate how well veliparib, radiation therapy, and temozolomide work in treating participants with newly diagnosed malignant glioma without H3 K27M or BRAFV600E mutations. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib, radiation therapy, and temozolomide ...

The purpose of this study is to assess the combination of INCMGA00012 with radiation therapy (RT) and bevacizumab with or without epacadostat in the treatment of recurrent glioblastoma (GBM). Regimen A of this study has been completed and Mayo Clinic will only be participating in the Regimen B portion.

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also block the growth of the tumor by blocking blood flow to the tumor. It is not yet known whether bevacizumab together with dasatinib are more effective than a placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme. ...

Intraoperative Microdialysis During Neurosurgery for Central Nervous System Malignancies

This phase I trial studies the side effects and the best dose of wild-type reovirus (viral therapy) when given with sargramostim in treating younger patients with high grade brain tumors that have come back or that have not responded to standard therapy. A virus, called wild-type reovirus, which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells. Sargramostim may increase the production of blood cells and may promote the tumor cell killing effects of wild-type reovirus. Giving wild-type reovirus together with sargramostim may kill more tumor cells.

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of WSD0922-FU in subjects with recurrent glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) and CNS metastases of non-small cell lung cancer (NSCLC).

The purpose of this study is to find out more about the side effects of rovalpituzumab tesirine (SC16LD6.5) and what doses of rovalpituzumab tesirine (SC16LD6.5) are safe for people with specific delta-like protein 3-expressing cancers.

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Review Article
Published: 11 March 2022

Advances in local therapy for glioblastoma — taking the fight to the tumour

Thomas S. van Solinge ORCID: orcid.org/0000-0003-3762-3618 1 , 2 ,
Lisa Nieland ORCID: orcid.org/0000-0002-4396-8252 1 , 2 ,
E. Antonio Chiocca 3 &
Marike L. D. Broekman 1 , 2 , 4

Nature Reviews Neurology volume 18 , pages 221–236 ( 2022 ) Cite this article

9536 Accesses

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Neurosurgery

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.

Glioblastoma almost always recurs at or near the resection cavity, within the radiotherapy field.

Local therapy provides a unique opportunity to deliver high doses of therapeutics to the area with the highest concentration of glioblastoma cells, with limited systemic adverse effects.

Many phase I and II trials experimenting with various forms of local therapy have been — and are being — conducted in glioblastoma, with many showing great potential for improving progression-free and overall survival.

Large randomized phase III trials comparing local therapies with standard of care have been hindered by high cost, labour intensity and challenges in patient recruitment.

Close collaboration between clinicians, researchers, companies and governmental institutions is needed to smooth the transition from laboratory to phase I and II trials to large-scale randomized controlled trials.

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Acknowledgements

The authors thank M. E. Haeflich for proofreading this manuscript for typographical and grammatical errors; skilled editorial assistance from S. McDavitt; and insights from X. Breakefield. M.L.D.B. is supported by grant NIH NCI R35 CA232103. T.S.v.S. is supported by grants from the Bontius Stichting, the Nijbakker-Morra Fund, Foundation Vrijvrouwe van Renswoude and the Bekker-la Bastide Fund. T.S.v.S. and E.A.C. are supported by NIH grant P01 CA069246.

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Thomas S. van Solinge, Lisa Nieland & Marike L. D. Broekman

Department of Neurosurgery, Leiden University Medical Center, Leiden, Netherlands

Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

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T.S.v.S. researched data for the article. All authors contributed substantially to discussion of the content. T.S.v.S and M.L.D.B. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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E.A.C. is currently an advisor to Advantagene, Alcyone Biosciences, Insightec, DNAtrix, Immunomic Therapeutics, Seneca Therapeutics, GlaxoSmithKline and Voyager Therapeutics and has equity interest in DNAtrix, Immunomic Therapeutics and Seneca Therapeutics; he has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, Shanghai Biotech and Sangamo Therapeutics. He has received research support from the NIH, the US Department of Defense, the American Brain Tumor Association, the National Brain Tumor Society, the Alliance for Cancer Gene Therapy, the Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics and Amgen. He is also a named inventor on patents related to oncolytic HSV-1 and non-coding RNAs. The other authors declare no competing interests.

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In December 2020, we searched PubMed and Embase for studies utilizing any form of local therapy in glioblastoma. Keywords, Mesh terms and Emtree terms including “glioblastoma”, “glioma”, “local therapy”, “localized therapy”, “convection enhanced delivery”, “thermotherapy”, “wafer”, “brachytherapy”, “photodynamic therapy” and their synonyms were combined to form our search. Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. Articles had to be written in English and published within the past 20 years. Studies performed before implementation of the Stupp protocol were excluded, unless deemed relevant to current studies or patient care. Case reports were also excluded. Additional papers were recommended by all authors. For current clinical trials, ClinicalTrials.gov was searched for disease “glioblastoma” and “glioma”, and all trials with status ‘not yet recruiting’, ‘recruiting’, ‘enrolling by invitation’, ‘active, not recruiting’, or ‘available’.

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van Solinge, T.S., Nieland, L., Chiocca, E.A. et al. Advances in local therapy for glioblastoma — taking the fight to the tumour. Nat Rev Neurol 18 , 221–236 (2022). https://doi.org/10.1038/s41582-022-00621-0

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Glioblastoma Foundation(R) Announces the Establishment of Groundbreaking Genomic Testing & Research Laboratory

DURHAM, NC / ACCESSWIRE / May 15, 2024 / The Glioblastoma Foundation announced today the establishment of a pioneering Genomic Testing & Research Laboratory , scheduled to open in the fall of 2024. This groundbreaking Lab aims to revolutionize glioblastoma treatment by giving patients greater access to comprehensive genomic testing services, as well as identifying drugs specific for their tumors.

Glioblastoma is the most aggressive and lethal form of brain cancer, with a median survival rate of just 12 to 18 months. Because each patient's glioblastoma is totally unique to them, uniform standards of care fail to have long-term effectiveness.

The goal of the Glioblastoma Foundation's new Genomic Testing & Research Laboratory is to offer state-of-the-art molecular testing services to patients to inform personalized treatment plans to improve survival and quality of life. The Glioblastoma Foundation aims to make these services available at a low cost, with the goal of significantly improving outcomes for those receiving what is now a devastating diagnosis.

Located in Durham, NC, the Lab will be equipped to receive tumor tissue samples from all over the continental U.S. and provide prompt test results starting this fall.

"As the leading organization dedicated to developing targeted treatments for glioblastoma, the Genomic Testing & Research Laboratory represents a significant step forward in the Glioblastoma Foundation's mission to transform glioblastoma from terminal to treatable," says Gita Kwatra, CEO of the Glioblastoma Foundation. "The Laboratory's advanced genomic testing services will be accessible to all patients across the U.S., at the lowest cost possible. Patients will also benefit from faster turnaround times-critical timing for patients with a prognosis of just months. The glioblastoma landscape hasn't materially changed in 30 years, with the five-year survival rate remaining below 10%. We foresee the Glioblastoma Foundation Genomic Testing & Research Laboratory transforming treatment, quality of life, and outcomes."

Gita Kwatra, PharmD, MBA, will lead the research laboratory, and Shari Brown, MD, a molecular pathologist, will direct the genomic testing.

Each year, approximately 15,000 people are diagnosed with glioblastoma. For more information about the Glioblastoma Foundation and the new Genomic Testing & Research Laboratory, please visit https://www.glioblastomafoundation.org/

About the Glioblastoma Foundation:

The Glioblastoma Foundation , established in 2016, aims to transform glioblastoma treatment and care through research, advocacy, and support initiatives. By funding innovative research projects, raising awareness, and providing resources for patients and families, the Glioblastoma Foundation strives to improve outcomes and quality of life for those affected by this aggressive form of brain cancer.

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Published: 13 May 2024

PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression

Yu-Chan Chang 1 ,
Ming-Hsien Chan 1 ,
Chien-Hsiu Li 2 ,
Chi-Long Chen 3 , 4 ,
Wen-Chiuan Tsai 5 &
Michael Hsiao 6

Cell Communication and Signaling volume 22 , Article number: 266 ( 2024 ) Cite this article

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Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).

Introduction

Glioblastoma (GBM) is a World Health Organization (WHO) grade IV malignancy and one of the most aggressive glial cell tumors of the central nervous system [ 1 ]. Objective evaluations suggest that standard therapy for GBM patients, which includes tumor resection, concurrent radiotherapy, and adjuvant chemotherapy with temozolomide (TMZ), does not result in long-term survivalas the median survival time is less than two years [ 2 ]. Many common biomolecules in glioblastoma (GBM) affect patient outcomes, including isocitrate dehydrogenase 1/2 (IDH 1/2), TP53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and O6-methylguanine DNA methyltransferase (MGMT) which contain genetic alterations [ 3 , 4 , 5 ]. Despite significant advancements in understanding the molecular mechanisms and in devising novel therapeutic protocols, numerous patients with GBM still exhibit low survival rates. Hence, GBM is viewed as a multifactorial tumor rather than as a condition linked to a single risk factor. Currently, GBM is categorized into three molecular subtypes (proneural, classical, or mesenchymal) according to its molecular characteristics [ 6 , 7 ]. These subtypes manifest distinctive gene mutations/expressions, clinical courses, and survival rates. Therefore, the identification of changes in transcription factors and expression patterns within each subtype can assist in investigating potential drug applications and signaling pathways.

Serotonin (5-HT), which regulates mood and emotions such as fear and happiness activates various serotonin receptors (5-HTR) upon release. Fourteen receptors within seven families of serotonin receptors have been defined [ 8 ]. Previous research has indicated that serotonin disrupts G-protein complex assembly, signaling cascades, and cAMP levels [ 8 ]. Various HTRs release diverse neurotransmitters, such as dopamine, norepinephrine, and serotonin [ 9 , 10 , 11 ]. Clinical studies have resulted in the generation of HTRs and selective serotonin reuptake inhibitors (SSRIs) as a means to hinder HTR function and inhibit serotonin reuptake [ 12 ]. Consequently, maintaining adequate levels of serotonin in the brain is vital. Previous studies have shown that serotonin can mediate a variety of events in GBM cells, including signaling pathway activity, the response to chemotherapy, and apoptosis/autophagy. [ 13 , 14 , 15 , 16 , 17 , 18 ]. Various 5-HTRs can increase serotonin levels and affect other signaling pathways, such as peroxisome proliferator-activated receptor gamma (PPARγ), which has been correlated with multiple brain-related diseases and conditions, such as stroke, cancer, and tranumatic brain injury [ 19 ]. PPARγ plays a regulatory role in anti-inflammatory mechanisms, oxidative stress, neuronal death, and glucose homeostasis [ 20 ]. Recent scientific studies have identified PPARγ as a therapeutic target in GBM patients [ 21 , 22 ]. For example, the PPARγ agonist, pioglitazone enhances performance. Furthermore, PPARγ may also contribute to a reduction in cancer phenotypes and characteristics induced by serotonin [ 23 ]. It is currently unclear whether the function of PPARγ regulating serotonin secretion is impaired in GBM. Nonetheless, research and medical interventions for GBM utilizing 5-HTR inhibitors and SSRIs are in progress [ 24 ].

Aldolase, an enzyme that plays a critical role in metabolism and glycolysis, has three isoforms: aldolase-A (ALDOA), aldolase-B (ALDOB), and aldolase-C (ALDOC) [ 25 ]. ALDOA is widely expressed in most cancers and is associated with poor survival [ 26 ]. The roles of ALDOB or ALDOC vary across different cancer types. Several studies have suggested that ALDOB can obstruct metastasis and invasiveness of hepatocellular carcinomas [ 27 ]. ALDOC is expressed in specific regions of the brain and its expression correlates with development, injury, and trauma. Suppressed ALDOC expression was observed in GBM, and this lack of expression was significantly correlated with various clinicopathological factors [ 26 ]. However, further investigation is necessary to determine the exact mechanism of action involved. In this study, we found that hypermethylation of the ALDOC promoter suppresses its expression. This, in turn, leads to abnormal serotonin production and deactivation of the PPARγ pathway, which results in malignant GBM. The incorporation of SSRIs and PPARγ agonists into current TMZ treatment regimens may yield positive outcomes. Accordingly, the ALDOC/PPARγ axis has become a significant component of GBM research, including the exploration of novel therapies.

Materials and methods

Cell culture and establishment of stable clones.

The CCF-STTG1 human glioblastoma cell line was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) (Invitrogen, Carlsbad, CA, USA). The human glioblastoma cell lines T98-G, U87-MG, and SVGp12 were cultured in EMEM supplemented with 10% FBS (Invitrogen, Carlsbad, CA, USA). The human glioblastoma cell lines A172, LN-229, Hs683, and U118-MG were cultured in DMEM supplemented with 10% FBS (Invitrogen, Carlsbad, CA, USA). The SW1088 human glioblastoma cell line was cultured in L-15 medium supplemented with 10% FBS (Invitrogen, Carlsbad, CA, USA). Cells were incubated in a humidified atmosphere, -containing 5% CO 2 with the exception of SW1088. The ALDOC sequence and pGIPZ lentiviral shRNA mir system (Thermo, Waltham, MA, USA) were utilized to establish stable cell line. ALDOC shRNA#1: 5’-GCAGCACAGTCACTCTACATT-3’ and the shRNA#2: 5’- CTCTACCAGAAAGATGATAAT-3’. The cells were infected with lentiviruses for two days after which. Puromycin (1 µg/ml, Sigma, St. Louis, MO, USA) was used to select stable clones for two weeks. The following cell lines were obtained from the ATCC cell bank: CCF-STTG1, U87-MG, T98-G, Hs683, U118-MG, A172, LN-229, SW1088, and SVGp12. The cells were all authenticated through short tandem repeat (STR) analysis, which produced profiled loci matches of more than 80%. An assay kit was used to confirm that all cell lines were mycoplasma-free for the purposes of this study.

In vivo model

The Institutional Animal Care and Use Committee (IACUC) of Academia Sinica approved all the animal studies (#21-12-1744). All animal experiments were performed according to the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (publication no. 85 − 23, revised 1996). Six-week-old male NOD-SCIDγ strain mice (JAXTM NOD-Cg-Prkdcscid Il2rgtm1Wjl/SzJ; NOD-SCIDγ) obtained from The Jackson Laboratory (Bar Harbor, ME, USA) and exhibited severe combined immunodeficiency (JAXTM NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ). To evaluate the in vivo tumorigenicity of U87-MG cells 5 × 10 4 cells were added to 3–5 µl of PBS -mixed with Matrigel (1:1 mixure) and stereotactically injected into the brains of the animal ( with the guide screw located 2.5 mm to the right and 1.5 mm above the bregma on the skull) [ 28 ]. The syringe was gradually lowered to a depth of 3 mm below the surface of the skull. After the needle entereds the brain, an electric pump was used to pass through the cells slowly at a rate of 1 µL/minute for 6–8 min to prevent any reverse flow. On the day of tumor injection, the mice were randomly assigned to groups, and various treatments were initiated: the vehicle group received PBS, while the treatment group received either a low dose (10 mg/kg) or a high dose (40 mg/kg) of GW0742 with or without TMZ (at a dosage of 20 mg/kg) via oral gavage seven times per week ( n = 8 mice per group). We measured the volume of the tumor and the body weight on a weekly basis. The tumor volume was calculated using the following formula: tumor volume = 1/2LW 2 . When the orthotopic tumor was removed after seven weeks, the cell fluorescence/luminescence signal at the endpoint was analyzed using IVIS. The survival time of each mouse was recorded, and survival curves were plotted according to the treatment group.

Case selection

Between 1997 and 2005, 50 patients were diagnosed with different grades of gliomas at the Tri-Service General Hospital in Taiwan. Our cohort contained 1 of grade 1_pilocytic astrocytoma, 3 of grade 2_oligodendroglioma, NOS, 1 of grade 2_astrocytoma, IDH-mutant, 1 of grade 2_glioblastoma, IDH-wildtype, 2 of grade 3_Oligodendroglioma, NOS, 2 of grade 3_Astrocytoma, IDH-mutant, 28 of grade 4_Glioblastoma, IDH-wildtype, 10 of grade 4_Diffuse midline glioma, H3 K27-altered and 2 of grade 4_Astrocytoma, IDH-mutant. A retrospective review of each patient’s medical records was used to collect clinical information and pathology data. All patients were diagnosed according to the World Health Organization (WHO) Classification of Central Nervous System Tumors (2021). Most patients had follow-up data, with the longest clinical follow-up time begin 60 months. The study at Tri-Service General Hospital (number 098-05-295) was approved by the Institutional Review Board after obtaining written informed consent from each patient who participated in the study.

Chemicals and antibodies

Inositol (catalogue number PHR1351) was acquired from Sigma (St. Louis, MO, USA). The anti-serotonin antibody was purchased from Abcam (catalog number ab66047). RS-127,445 (item number R2533) and serotonin powder (item number H9523) were both obtained from Merck (Kenilworth, NJ, USA). GW0742 (item number S8020) and Pioglitazone (item number AD-4833) along with asenapine maleate (item number S1283) and myo-inositol (item number S4530) were purchased from Selleckchem (Houston, TX, USA). A DMSO solution was used to dissolve all the chemicals.

Bisulfite conversion and methylation-specific PCR

Genomic DNA was isolated from GBM cells at 85% confluent using the DNeasy Blood & Tissue Kit (Qiagen, 69,504). Bisulfite conversion was performed using the EpiJET Bisulfite Conversion Kit (Thermo Scientific, #K1461) according to the manufacturer’s instructions. PCR amplification of bisulfite converted DNA was performed using Phusion U Hot Start DNA Polymerase (Thermo Scientific, F555S) with specific primers designed by- MethPrimer and MethylPrimer Express. After PCR amplification, the samples were purified, and the methylation status was assessed by visualization on a 3% agarose gel.

Immunofluorescence microscopy

The cells were cultured in 8-well chamber slides, fixed in 4% paraformaldehyde, permeabilized, and then exposed to primary antibodies, followed by incubation with secondary FITC- or Alexa Fluor 594-conjugated anti-mouse or anti-rabbit antibodies. The slides were examined, and images were captured with a Zeiss LSM 510 META microscope (Carl Zeiss, Jena, Germany). The nuclei were stained with 4’,6-diamidino-2-phenylindole (DAPI) to aid in visualization of the cells.

Ingenuity pathway analysis (IPA)

A 1.5-fold change was dected for shALDOC-1 and shALDOC-2 compared with vector control samples based on the expression values from microarray chips. The aforementioned values were imported into IPA for analysis of upstream regulators. According to the IPA results (Supplementary Table 5 ), activated upstream regulators are shown in orange, while inhibited upstream regulators are showen in blue.

In silico analysis

Clinical information and genomic matrix files were downloaded from the Cancer Genome Atlas (TCGA) database using the UCSC cancer browser website ( https://genome-cancer.ucsc.edu/proj/site/hgHeatmap/ ) and from the Chinese Glioma Genome Atlas (CGGA) database using the GlioVis website ( https://gliobis.bioinfor.cnio.es/ ) by clinicians and researchers. The GEPIA website ( https://gepia.cancer-pku.cn/index.html ) was used to assess the expression levels of genes in the different groups. All CCLE comprehensive datasets (RNA-seq gene expression, methylation, and metabolomics data) were downloaded from the CCLE website and analyzed using Prism software. Statistical analysis was performed using SPSS 17.0 software (SPSS, Inc., Chicago, IL, USA). Statistical differences between the two groups were analyzed using either a paired t-test or a Mann-Whitney U test. p values less than 0.05-indicated statistical significance.

RT-quantitative PCR

The cells were lysed using TRIzol reagent (Invitrogen, Carlsbad, CA, USA), and total RNA was extractedaccording to the manufacturer’s instructions. Nanodrop spectrophotometer (Thermo, Waltham, MA, USA) was used to determine the quantity of RNA. Reverse transcription-PCR (RT-PCR) was performed using a SuperScript III kit (Invitrogen, Carlsbad, CA, USA), according to manufacturer’s instructions. To obtain a standardized expression level, the expression of target genes was compared with that of ribosomal protein S26, which served as an internal control. All primers were designed by referencing PrimerBank and previous publications (refer to Supplementary Table 5 ). MSP and BSP primers were designed using the MethPrimer website.

Western blot

The cells were lysed in RIPA buffer for 30 min and then centrifuged at 13,000 rpm for 15 min at 4 o C. The membrane/cytoplasmic protein fractions of the cultured cells were obtained using the Mem-PER Plus Membrane Protein Extraction Kit (Thermo, Waltham, MA, USA). The protein concentration was measured using a BCA protein assay (Thermo, Waltham, MA, USA). Total proteins (30 µg) were separated by SDS-PAGE on 10% polyacrylamide gels and transferred to PVDF membranes. The membranes were hybridized with primary antibodies overnight after blocking for 30 min in 5% nonfat milk. Immunoblotting was performed with primary antibodies against DNMT1 (GeneTex, Hsinchu City, Taiwan), p-Akt (Cell Signaling Technology, Danvers, MA, USA), Akt (Cell Signaling Technology, Danvers, MA, USA), HTR2B (GeneTex, Hsinchu City, Taiwan), ALDOC (Abcam, Cambridge, UK), PPARγ (Abcam, Cambridge, UK), PTGS2 (GeneTex, Hsinchu City, Taiwan), NR2F1 (GeneTex, Hsinchu City, Taiwan) and β-actin (Sigma, St. L ouis, MO, USA). A chemiluminescence system was used to visualize the immunoreactive bands (Amersham ECL PlusTM, GE Healthcare Life Sciences, Chalfont St. Giles, UK).

Analysis of microarray gene expression data and microarray data collection

We isolated RNA (1–2 µg) from GBM cells infected with shLuc or shALDOC lentivirus using an RNeasy Mini kit. Affymetrix GeneChip products (human genome U133A plus 2.0) were used per the GeneChip User Manual to synthesize cRNA from total RNA and hybridize and scan microarrays. We normalized the raw gene expression data and used R-project statistical software ( http://www.r-project.org/ ) coupled with Bioconductor packages to conduct the analysis. We used the t statistic to generate a cutoff value of > 1.5 fold changeand applied this value as the threshold to determine gene candidates that were differentially expressed between the control and overexpression models after RMA normalization (Supplementary Table 2 ). Finally, we uploaded the list of predicted upstream regulators and canonical pathways (found using IPA to Ingenuity.

Construction of genes and production of lentiviruses

We obtained the lentiviral envelope and the packaging plasmid (pMDG and p △ 8.91) from the National RNAi Core Facility (Academia Sinica, Taiwan). CLONTECH (CA, USA) provided the ALDOC lentiviral shRNA constructs and the nonsilencing pGIPZ, an shRNA construct that does not bind to target DNA. Using a calcium phosphate transfection method, lentiviruses together with pM.DG, p △ 8.91 and the shRNA construct were cotransfected into 293T cells. The cells were incubated for 48 h and then infected with polybrene (2 g/ml) after the lentiviruses were harvested. Puromycin (2 µg/ml) was used for one week to select cells with altered ALDOC expression. For further experiments, a useful GL reporter gene (luciferase + green fluorescent reporter gene) plasmid was also prepared to infect ALDOC two-way stable cells.

Migration and invasion assays using in a Boyden chamber

The migration experiment was performed on polycarbonate filters (GE Healthcare Life Sciences, Chalfont St. Giles, UK) using human fibronectin (1 mg/ml) from Sigma (St. Louis, MO, USA). In each well in the lower part of the Boyden chamber, 10% FBS was added to the cell culture medium. In all, 1.5 × 10 4 cells in serum-free culture medium were seeded into each well corresponding to the upper part of the Boyden chamber. For the invasion experiment, 10% Matrigel (BD Biosciences, San Jose, CA, USA) was applied to the other side and mixed with human fibronectin at a concentration of 1 mg/ml. The lower part of the Boyden chamber was filled with culture medium containing 10% FBS. Each well of the Boyden chamber was seeded with cells in serum-free medium. After a specified time (migration: 8 h, invasion: 14 h), the insert was removed and the cells were stained with Giemsa solution and counted under a light microscope (400x, 8 random fields per well). Three independent experimental replicates and four replicates of each sample were included.

Analysis of glucose uptake and lactate production

A colorimetric glucose and lactate assay kit (BioVision, Milpitas, CA, USA) was used to measure glucose consumption and lactate production according to the manufacturer’s instructions. Briefly, cells (intracellular metabolites) from the specified experiments were incubated with assay buffer containing enzymes and glucose/lactate probes. Optical densities were then determined at wavelengths of 570/450 nm. Cell numbers were calculated and normalized to the background.

Cell viability assays

A Trevigen tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) cell proliferation assay kit was used to assess cell viability according to the manufacturer’s instructions (Trevigen, Gaithersburg, MD, USA). In proliferation and cytotoxicity assays, MTT is used to determine cell viability. Cells were seeded into 96-well microplates at a density of 2,000 cells/100 mL of culture medium. After seeding, the cells were treated for 24, 48–72 h with dimethyl sulfoxide (DMSO) as a control or with different doses of drugs. A microplate reader (Spectral Max250; Molecular Devices, Sunnyvale, CA, USA) was used to measure the optical density at 570 nm after the cells were incubated for 4 h in medium containing MTT and lysed with DMSO.

Tissue microarray and immunohistochemistry

We prepared a TMA containing GBM tissue and a small amount of corresponding adjacent noncancerous brain tissue. For each patient, we selected three 1 mm cores from different areas of the tumor tissue. A pathologist evaluated the histopathological diagnosis of all samples using hematoxylin and eosin-stained slides. Serial 5-µm thick sections of tissue microarrays (TMAs) were stained using an automated immunostainer (Ventana Discovery XT autostainer, Ventana Medical Systems, Tucson, AZ, USA). Sections were first dewaxed in an oven at 60 o , deparaffinized in xylene and rehydrated in graded alcohol solutions. Heat-induced antigen retrieval was performed using Tris-EDTA buffer (pH 8.0) for 30 min. Staining was performed with a rabbit polyclonal anti-human ALDOC antibody (1:400, Cat.T0906, Abcam (Epitomics), Cambridge, UK) and with antibodies against, PTGS2 (1:100, GTX00656, GeneTex, Hsinchu, Taiwan) and NR2F1 (1:250, GTX4801, GeneTex, Hsinchu, Taiwan).

Interpretation of tissue microarray staining by immunohistochemistry

An independent pathologist blinded to patient outcome assessed the IHC staining. The only IHC signals detected in the cytoplasm and nuclei of tumor cells were those associated with aldolase family members. A tissue microarray was used to score the tumor for ALDOC/PTGS2 expression based on intensity scores of 0, 1 or 2. The percentage scores were calculated based on a scale of 0 ∼ 100. Finally, we used the intensity X percentage to determine the total IHC score and then used a 50% cutoff for the high- and low- expression groups. Immunoreactivity was recorded in terms of both intensity and percentage. The method for interpreting immunostaining was described in a previous study. A score of 0 was defined as the absence of cytoplasmic staining or cytoplasmic staining in less than 5% of the tumor cells. Patients with a score of two or more points were considered to have high expression. A score of 0 or 1 + represents low expression of the candidate gene and indicates loss of expression.

Statistical analysis

The nonparametric Mann-Whitney U test was used to analyze the statistical significance of differences among three independent experiments. SPSS 17.0 software (SPSS, Chicago, IL, USA) was used for statistical analysis. A paired t-test was used to compare the levels of ALDOC/PTGS2 expression by IHC in cancer tissues with those in adjacent normal tissues. Pearson’s chi-squared test was used to identify associations between clinicopathological categorical variables and ALDOC/PTGS2 IHC expression levels. The Kaplan-Meier (KM) method was used to estimate survival rates, and the log-rank test was used for comparisons. Patients lost to follow-up were censored from the follow-up period. Multivariate and univariate analyses were performed using Cox proportional hazards regression analysis with or without adjustment for tumor stage, lymph node stage and metastasis, and ALDOC/PTGS2 expression levels. All differences were considered significant at a P value of 0.05.

Hypermethylation and loss of ALDOC function in GBMs

This study examined alterations in ALDOC expression in different subtypes of brain cancer. Our analysis revealed a significant decrease in ALDOC expression was found in patients with WHO stage II and III low-grade glioma (LGG) as well as WHO stage IV glioblastoma (GBM) compared with nontumor samples (Fig. 1 A). Further classification revealed that ALDOC was generally less frequently expressed in GBM than in oligodendrogliomas, astrocytomas, and LGGs (Fig. S1 ). This article describes several common genetic alterations. The manifestations of ALDOC expression can be determined by the IDH1 mutation status or by the codeletion events of chromosome 1p/19q (Fig. 1 B). The pancancer profile also demonstrated lower ALDOC expression levels in brain tumors, such as gliomas, medulloblastomas, and meningiomas, than in other cancer types (Fig. 1 C). Therefore, the ALDOC expression level is closely associated with the occurrence of brain cancer.

Hypermethylation and loss of ALDOC function in GBM cells. ( A ) The expression level of ALDOC according to the WHO classification of brain tumors. This database extracted ALDOC profiles from CGGA RNA-seq files. ( B ) The expression level of ALDOC in GBM patients with several genetic alterations. This database extracted ALDOC profiles from CGGA RNA-seq files. ( C ) ALDOC expression levels across multiple cancer. Red indicates glioma-related tumors. This database extracted ALDOC profiles from CCLE RNA-seq files. ( D ) ALDOC methylation level across multiple cancers from the CCLE website. Red indicates glioma-related tumors. This database extracted ALDOC profiles from CCLE DNA methylation files. ( E ) Correlation diagram showing the ALDOC methylation level of a specific fragment (17:26903951–26,904,951) and the expression level (Spearman’s rho=-0.774, p = 7.7e-09). This database extracted ALDOC profiles from CCLE GBM cell line files. ( F ) Characterization of the methylation status of ALDOC in various GBM cell lines (T98G, U-87MG, and LN-229) by methylation-specific PCR. ( G ) Characterization of the methylation status of ALDOC in untreated LN-229 cells and those treated with 5-Aza (1 µM and 10 µM) treatment by methylation-specific PCR. ( H ) Quantification of the percentage of CpG sites in the ALDOC promoter region (17:26903951–26,904,951) in various GBM cell lines by bisulfite-specific PCR and pyrosequencing. This database extracted ALDOC methylation status data from CCLE GBM cell line files. ( I ) DNMT1, DNMT3 and ALDOC protein levels in untreated GBM cells and those treated with 5-Aza. The data from three independent experiments are presented in F , G , and I

Recent studies have indicated that the ALDOC promoter region is methylated [ 29 ]. This could affect the levels of ALDOC RNA, and therefore, it is hypothesized that the promoter region plays a crucial role in ALDOC silencing. To evaluate the degree of methylation, in silico analyses were conducted. The pancancer profile revealed increased methylation levels in certain intracranial malignancies (Fig. 1 D). After the correlation between the ALDOC methylation status and RNA expression level was analyzed in GBM cell lines, a significant negative correlation was found in GBM cell lines according to the Cancer Cell Line Encyclopedia (CCLE) (Spearman’s rho = -0.774, pvalue = 7.7e-09) (Fig. 1 E). To confirm these findings, three distinct GBM cell lines with varying methylation levels were selected. Our study revealed that the ALDOC gene is hypermethylated in T98G cells, while U-87 MG cells exhibit hypomethylation, and LN-229 cells exhibit an intermediate level of methylation, as detected by methylation-specific PCR (Fig. 1 F). Furthermore, our findings suggested that the methylation levels in LN-229 cells decreased in a dose-dependent manner after treatment with the demethylating agent 5-Azacitidine (5-Aza) (Fig. 1 G). Methylation-specific PCR (MSP) assays designed to amplify and characterize predicted methylation events. We furtehr review the assessment of methylation by bisulfite-specific PCR (BSP) amplification and sequencing. Our results indicated that the ALDOC promoter was hypermethylated in the A172 and LN-229 cell lines, while the ALDOC promoter was hypomethylated in the U-87MG, CCF-STTG1, and SW1088 cell lines (Fig. 1 H). These results are consistent with the MSP analysis and CCLE profile results. Furthermore, DNMTs mainly regulate DNA methylation regulation. After 5-Aza treatment, DNMT1 and DNMT3 protein expression was reduced, while ALDOC expression was restored in GBM cells (Fig. 1 I). These findings indicate that reduced ALDOC expression in GBM is due to hypermethylation.

ALDOC triggers metabolic reprogramming in GBM cells

To assess the impact of ALDOC loss of function and to validate the in silico results, we examined the endogenous protein level of ALDOC in multiple GBM cell lines (Fig. 2 A). Subsequently, we generated stable cell lines for ALDOC overexpression and knockdown using suitable cells. A172 and LN-229 cells were utilized to overexpress ALDOC, while U87-MG and SW1088 cells were used for ALDOC knockdown (Fig. 2 B and D). Since ALDOC is involved in glycolysis, we collected equal amounts of cells from each group of ALDOC knockdown cells to perform ELISA for the measurement of glucose, lactate, and ATP levels. Notably, our results demonstrated no significant differences in lactate and ATP production or glucose utilization rates compared with those of the controls (Fig. 2 E and S2A). Likewise, no important changes in metabolic activity were detected in the group treated with 5-Aza (Fig. S2 B).

The CCLE metabolomics platform was used to investigate further metabolites linked to ALDOC expression [ 30 ]. This particular dataset contains measurements of several metabolites across multiple cell lines. Each metabolite can be produced and evaluated in relation to past events, such as methylation and expression. Earlier studies have shown connections between diverse events, such as methylation and expression levels of specific genes, with carbohydrates, amino acids, and lipids [ 31 ]. In this study, we investigated the correlation between ALDOC expression events and cellular metabolite concentrations to identify potential dependencies. Our results revealed a negative correlation between ALDOC expression and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) (Fig. 2 F). In contrast, ALDOC methylation events were negatively correlated with ALDOC expression and were positively correlated with the concentrations of the aforementioned metabolites (Fig. S3 ). Changes in ALDOC methylation and expression were observed in GBM cell lines. The metabolites myo-inositol and serotonin underwent significant changes (Fig. 2 G). These findings suggest that GBM cells undergo metabolic reprogramming due to ALDOC loss of function or methylation.

ALDOC regulates various metabolic events and metabolites in GBM. ( A ) Immunoblotting was used to determine the levels of endogenous ALDOC proteins in GBM cell panels. Actin served as the internal control. ( B ) Quantification of the expression level of ALDOC in ALDOC two-way (overexpressing and knockdown) stable cells by RT-qPCR. ( C ) Protein levels of ALDOC in two ALDOC-overexpressing stable cell lines, LN-229 and A172, were analyzed by immunoblotting. Actin served as the internal control. ( D ) Protein levels of ALDOC in two stable ALDOC-knockdown stable cell lines, U87-MG and SW1088, were analyzed by immunoblotting. Actin served as the internal control. ( E ) ATP concentration and lactate production in a stable ALDOC-knockdown U87-MG cell model. ( F ) Computation-dependent association analysis was performed in GBM cells using metabolite concentrations and ALDOC expression, and events with significant differences were screened. Spearman’s nonparametric method was used to determine the significance of the associations. This database extracts transcriptomic and metabolomic data from CCLE omics files. ( G ) The heatmap shows the methylation status, ALDOC expression level, and inositol/serotonin production in the GBM cell panel. This database extracted various profiles from CCLE omics files. The means and standard errors from three independent experiments are presented in B and E. The Mann-Whitney U -test was used to analyze the significance of the difference; *** p < 0.001

Dysfunction of ALDOC in GBM results in serotonin production and pathway activation

To examine the impact of ALDOC and the aforementioned metabolites, we assessed various cancer characteristics using cell models in which ALDOC was either overexpressed or suppressed. We observed significant disparities in migration/invasion, but not in proliferation (Fig S4 A). ALDOC expression repressed invasion compared with control cells, whereas reduced ALDOC levels were linked to elevated migration/invasion abilities (Fig. 3 A and S4B-C).

Previous metabolite profiles were analyzed to investigate the correlation between these changes and serotonin alterations. Our findings indicate that the CCF-STTG1, U87-MG, and SW1088 cell lines exhibited reduced serotonin production (< 5, serotonin metabolite abundance, log10 scle), whereas the Hs683 cell line displayed moderate serotonin production, and the LN-229, SF126, and A172 cell lines exhibited increased serotonin production (> 5, serotonin metabolite abundance, log10 scle) (Figs. 2 G and 3 B). The concentration of measured serotonin was significantly reduced in the ALDOC overexpressing group (Fig. 3 C). The addition of serotonin to the cell cultures at low concentrations increased the invasiveness and proliferation of GBM cells (Fig. 3 D and E and S5 ). We also used fluorescent labeling of serotonin in cell models [ 32 ]. A significant increase in the signal in and around the nucleus was observed with the addition of serotonin. ALDOC inhibition resulted in an even greater increase in serotonin expression (Fig. S6 ). We further examined the prospective functions of serotonin in GBM models, but the introduction of serotonin alone did not influence the response of GBM cell lines to TMZ (Fig. S7 ). Additionally, myo -inositol was formerly recognized as a possible contender, but this compound did not have any noteworthy impact on the GBM cell phenotype (Fig. S8 ).

To confirm the role of serotonin in transsynaptic signaling through the HTR, we conducted qRT-PCR screening of all 5-HTR members, including those utilized by other neurotransmitters such as dopamine and epinephrine. Our findings revealed that serotonin application led to intensified activation of HTR2B and HTR4 expression levels (Fig. 3 F). We additionally explored conventional neurotransmitter signaling pathways and observed that serotonin treatment increased Akt phosphorylation (Fig. 3 G). Furthermore, we have identified the serotonin-specific transporter, SLC6A4, whose expression is in sync with serotonin concentration (Fig. 3 H and I). Our research using the ALDOC biphasic cell model confirmed the regulation of HTR2B and HTR4 expression levels by ALDOC (Fig. 3 J and K). Our findings demonstrate that ALDOC hypermethylation or dysfunction promotes GBM cell migration and invasion via serotonin and its receptors.

ALDOC regulates migration/invasion capabilities and the response to serotonin in GBM. ( A ) Migration/invasion ability of A172 cells expressing the exogenous vector or overexpressing ALDOC. Scale bar: 100 µM. ( B ) Bar graphs showing serotonin levels in GBM cell lines from CCLE metabolite profiles. We downloaded the results from the CCLE metabolomics pattern and customized low and high serotonin production in GBM cell lines. ( C ) Serotonin concentration of A172 cells expressing the exogenous vector or overexpressing ALDOC. ( D ) After exposure to serotonin, U-87MG cells were subjected to Giemsa staining to evaluate their migration ability (1 µM and 10 µM) treatment. Scale bar: 100 µM. ( E ) Serotonin concentrations in untreted U-87MG cells and thoese treated with serotonin (1 µM and 10 µM). ( F ) The expression level of HTR members in the serotonin treatment group. ( G ) The levels of p-Akt, Akt, and HTR2B in U-87MG cells treated with serotonin were determined by Western blot analysis to change in a dose-dependent manner. ( H ) The expression level of SLC6A4 in the ALDOC-knockdown and overexpression models. ( I ) The expression level of SLC6A4 in the serotonin treatment group. ( J ) Quantification of HTR2B expression levels in ALDOC two-way (overexpressing and knockdown) stable cells by q-PCR. (K) Quantitative analysis of the expression of HTR4 in ALDOC two-way cells (overexpressing and knockdown). In A, B, C, D, E, F, G, H, J and K, the means ± SEM of three independent experiments are presented. A nonparametric Mann-Whitney U -test was used to determine the significance of the differences. The blue column in A represents cellular migration, while the green column represents invasion ability. * p < 0.05; ** p < 0.01; *** p < 0.001

Loss of ALDOC function in GBM also affects PPARγ signaling

Serotonin is secreted and transmitted via 5-HT receptors to regulate downstream factors. An ALDOC-knockdown model with two independent clones was used in the GBM study to establish transcriptome profiles and to identify the primary pathway of influence. Probes were normalized and a cutoff value of > 1.5 fold change was set for further prediction (Fig. 4 A). The study revealed that 689 probes overlapped in two independent shALDOC versus control events (Fig. 4 B). IPA predicted that the inhibition of ALDOC would also inhibit the PPARγ signaling pathway (Fig. 4 C). Studies have suggested that the expression of genes downstream of PPARγ, such as IL1A, ILRL1, NR2F1, and PTGS2 [ 23 , 33 ], may be influenced by serotonin metabolism. Thus, the expression levels of these genes were analyzed. The results of our study indicate that ALDOC-knockdown resulted in alterations in downstream factors that corresponded with the previous transcriptomic profile (Fig. 4 D and Table S1 ). Conversely, the overexpression model exhibited an inverse trend (Fig. S9 ). Additionally, the inhibition of ALDOC suppressed PPARγ expression and the expression of downstream candidate factors (Fig. 4 E). Among these factors, our focus was on NR2F1 and PTGS2. Our research using the ALDOC expression model highlights the importance of regulating the PPARγ-NR2F1/PTGS2 pathway.

We again used a cell model with added serotonin and observed a dose-dependent decrease in PPARγ expression in the GBM cell model following serotonin treatment. Furthermore, the downstream genes IL1A, ILRL1, and PTGS2 were upregulated, while NR2F1 protein activation was reversed (Fig. 4 F-G). Upon administration of the HTR inhibitors/antagonists RS-127,445 and asenapine maleate (AM), PPARγ was reactivated (Fig. 4 H). Treatment with these inhibitors significantly suppressed GBM cell migration, serotonin concentration, and fluorescence signals (Fig. 4 I and J). We then performed a rescue experiment to investigate whether the addition of serotonin could reactivate the HTRs, potentially reducing the effect of the antagonists (Fig. S10 ). Our findings indicate that serotonin disrupts and inhibits PPARγ signaling in GBM and that this disruption is regulated by ALDOC.

A reduction in ALDOC function is expected to decrease PPARγ signaling and its downstream targets. ( A ) The volcano plot reveals the candidate selection criteria for shALDOC versus the vector control in U-87MG cells. ( B ) The Venn diagram shows the common signatures (689 probes) between shALDOC-1 vs. control and shALDOC-2 vs. control for further interpretations. ( C ) The highest-ranking potential regulatory pathways from the common signature of shALDOC were predicted by IPA. ( D ) Quantification of the expression levels of PPARγ downstream targets ( IL1A , ILRL1 , NR2F1 , and PTGS2 ) in stable ALDOC-knockdown cells by q-PCR. ( E ) The protein levels of ALDOC, PPARγ, and its downstream targets (NR2F1, PTGS2, IL-1 A and ILRL1) in stable ALDOC-knockdown cells were detected by immunoblotting. Actin served as the internal control. ( F ) Quantitative PCR was used to quantify the dose-dependent changes in the expression levels of PPARγ downstream targets ( IL1A, ILRL1 and PTGS2 ) in U-87MG cells. ( G ) The protein levels of PPARγ and its downstream targets (NR2F1, PTGS2, IL-1 A and ILRL1) in U-87MG cells increased in a serotonin dose-dependent manner. Actin served as an internal control purposes. ( H ) The protein levels of PPARγ and its downstream target PTGS2 in LN-229 cells treated with or without 5-HT receptor inhibitors (RS-127,445 and AM) were detected by immunoblotting. Actin served as an internal control. ( I ) Serotonin concentration in U-87MG shALDOC cells treated with 5-HT receptor inhibitors (RS-127,445, 10 µM and AM, 100 µM) treatment. ( J ) Immunofluorescence assay of U-87MG shALDOC cells after RS-127,445 treatment. Red: serotonin; Blue: DAPI. Scale bar: 20 µM. AM: Asenapine maleate. In D, F, and I, the means ± standard error of the means are presented for three independent experiments. A nonparametric Mann-Whitney U -test was used to determine the significance of the difference; * p < 0.05; ** p < 0.01; *** p < 0.001

Modulation of the ALDOC-PPARγ axis can reduce in situ brain tumorigenicity and prolong survival

To evaluate the medical significance of ALDOC in animal models of GBM, we conducted in vivo tumorigenicity studies. We intracranially injected LN-229 cells and ALDOC-overexpressing cells into the mice. These cells were equipped with dual reporter genes (green fluorescent/luciferase) to ensure that the conditions were consistent among all groups during the study. Ultimately, we measured the photon counts of all groups using an in vivo imaging system (IVIS) at the endpoint. Compared with that in the vector group, the luminescence signal in the ALDOC-overexpressing group was decreased (Fig. 5 A). Moreover, the ALDOC overexpressing group had a lower photon count than the whole-brain extraction group (Fig. 5 B). Weekly real-time monitoring indicated that ALDOC reduced the in situ growth capability of GBM without affecting body weight (Fig. 5 C and D). Compared with the control group, the group that received cells that overexpressed ALDOC had longer survival times (Fig. 5 E).

To investigate particular regions of target proteins, we divided the whole brain and performed multiplex immunohistochemistry (IHC). The results indicated that in the animal experiments, the expression of ALDOC and the PPARγ downstream factor NR2F1 was significantly higher in the ALDOC overexpressing group than in the vector control group (Fig. 5 F& S11). Additionally, we incorporated RS-127,445 into the above orthotopic brain tumor model. Additionally, the results indicated a significant decrease in serotonin (Fig. 5 H) and related molecules, accompanied by the restoration of ALDOC and NR2F1 expression (Fig. 5 I), in addition to the inhibition of tumor growth (Fig. 5 G). These findings highlight the importance of both the ALDOC and PPARγ pathways in an in vivo GBM model.

ALDOC modulates orthotopic tumor growth in GBM animal models. ( A ) An overview of an intracranial LN-229 cell injection at the first IVIS tracking signal (2nd week) between the vector group and the ALDOC overexpressing group. ( B ) Overview of the intracranial model at the endpoint in the vector and ALDOC overexpressing groups after whole-brain extraction. Quantification of the whole brain. ( C ) Continuous radiance quantification of the intracranial LN-229 cell model in the vector and ALDOC overexpression groups. ( D ) Continuous body weight quantification in the vector and ALDOC overexpression groups. ( E ) To establish an orthotopic brain model, six-week-old NOD/SCID gamma mice were injected intracranially with LN-229 cells expressing the vector control or ALDOC-overexpressing LN-229 cells. Kaplan-Meier plots of the time to death, are presented for the vector-treated or ALDOC-overexpressing mice. n = 6 per group, p -value = 0.011. ( F ) After whole-brain extraction, representative multiplex IF for several candidate proteins in the LN-229 and LN-229 shALDOC intracranial models was performed. Red: NR2F1; Green: ALDOC; Blue: DAPI. Scale bar: 150 µM. ( G ) IVIS luminescence imaging system detection in the solvent group and the 10 µM RS-127,445 group after whole-brain extraction in the LN-229 intracranial model. ( H ) Serotonin concentration in the solvent group or the 10 µM RS-127,445 group. ( I ) Quantitative PCR was used to quantify the expression levels of targets ( SLC6A4, HTR2, ALDOC, PTGS2 and NR2F1 ) in LN-229 cells after RS-127,445 treatment. A non-parametric Mann-Whitney U -test was used to determine the significance of the difference. *** p < 0.001

PPARγ agonists have therapeutic potential in GBM models

Although initial results suggest the clinical potential of HTR antagonists and SSRIs, these medications have limitations and may cause side effects. Therefore, we propose that enhancing PPARγ signaling could be an alternative therapeutic strategy. We treated ALDOC-knockdown cells with the PPARγ agonists GW0742 and pioglitazone [ 18 ], which resulted in a significant decrease in migration ability compared with that of the solvent control (Fig. 6 A). Moreover, the group treated with the PPARγ agonists, particularly GW0742, exhibited decreased serotonin production at doses that did not impact cytotoxicity (Fig. S12 ). Furthermore, in the shALDOC model cotreated with serotonin and GW0742, the inhibition of PPARγ by serotonin decreased the efficacy of GW0742 (Fig. S13 ). To investigate the interplay of HTR antagonists as described earlier, we utilized RS-127,445 and GW0742 in a cell model in which ALDOC was knocked down. Western blot analyses demonstrated that agonists restored the expression of PPARγ and its downstream components (Fig. 6 B & S14 ). These results suggest that PPARγ agonists are markedly more effective than HTR antagonists.

TMZ, a typical treatment option, was used to evaluate whether HTR antagonists or PPARγ antagonists were more effective. Our results revealed a negative correlation between the IC50 of TMZ and ALDOC/PPARγ expression (Fig. S4 . This is in agreement with our actual experimental results. In a cell line that highly expresses ALDOC (U-87 MG), RS-127,445 alone did not enhance the effects of TMZ treatment, but the addition of GW0742 exerted significant effects (Fig. 6 C). However, in cells with low ALDOC expression (A172), the overexpression of ALDOC was significant as was the treatment with GW0742 (Fig. 6 D). In the animal model, after 28 days of treatment with TMZ combined with GW0742, the size of in situ tumors in the combined treatment group was significantly reduced compared with that in the group that was treated with TMZ alone (Fig. 6 E). More importantly, we observed a doubling of survival time in the current animal model (Fig. 6 F). In addition, the TMZ + GW0742 group demonstrated that ALDOC and NR2F1 actually restored potency (Fig. 6 G). This finding suggests that PPARγ agonists in combination with TMZ may be a viable treatment option for GBM and that the expression of ALDOC should be carefully evaluated.

PPARγ agonists can reverse the phenotype caused by ALDOC loss in vitro and in vivo. ( A ) The ability of U-87MG shALDOC cells to migrate with or without PPARγ agonists was assessed by Giemsa staining (GW0742 and pioglitazone). Scale bar: 100 µM. ( B ) The protein levels of PPARγ and its downstream targets (NR2F1 and PTGS2) in U-87MG ALDOC-knockdown stable cells were detected by Western blotting, with or without RS-127,445/GW0742 treatment. Actin was used as an internal control. ( C ) Alamar blue assay was used to measure cell viability in U-87MG cells treated with TMZ in a dose-dependent manner and treated with GW0742 or RS-127,445. ( D ) Alamar blue assay was used to measure cell viability in an A172 TMZ dose-dependent manner with GW0742 or ALDOC overexpression combined with GW0742. ( E ) An IVIS imaging system detected the TMZ alone group or the TMZ combined with GW0742 group in the U-87MG shALDOC intracranial model. ( F ) Kaplan-Meier plots showing the survival time of each group after the U-87 shALDOC cell line was used to restablish an orthotopic brain model and after treatment with TMZ or TMZ combined with GW0742. n = 8 for each group, p -value = 4.17e-4. ( G ) Representative multiplex IHC for several candidate proteins in the intracranial LN-229 cell model treated with TMZ alone or in combination with GW0742. Red: NR2F1; Green: ALDOC; Blue: DAPI. Scale bar: 150 µM. In A and C, the means ± standard errors of the means are presented for three independent experiments. A nonparametric Mann-Whitney U-test was used to determine the significance of the differences. * p < 0.05; ** p < 0.01; *** p < 0.001

The ALDOC-PPARγ axis can serve as a prognostic factor for patients with GBM

To examine the role of ALDOC or PPARγ signaling in GBM clinical cohorts, we examined additional clinical events recorded in the TCGA glioma dataset. To examine the role of ALDOC or PPARγ signaling in GBM clinical cohorts, we assessed additional clinical data from the TCGA glioma dataset. As previously confirmed, PPARγ triggers NR2F1 and suppresses PTGS2 (Fig. 4 D and E). We investigated the potential roles of ALDOC, HTR2B, PTGS2, and NR2F1 along with various clinicopathological factors of GBM, including EGFR amplification, PTEN deletion, and chromosomal abnormalities (including codeletion of 1p/19q, gain of chromosome 7, and loss of chromosome 10). These factors were used to divided patients into LGG and GBM groups based on the expression levels of our candidates, which varied by classification (Fig. 7 A). The heatmap indicated that the expression of HTR2B did not differ significantly from that of the other candidates. In contrast, ALDOC showed a negative correlation with PTGS2 and a positive correlation with NR2F1. Focusing the GBM type, ALDOC was found to be associated with PTGS2 and NR2F1 in both the TCGA (Fig. 7 B) and CGGA (Fig. S16 ) cohorts. This study reports on new prognostic markers related to ALDOC. Although prior research has highlighted its importance [ 34 ], we evaluated ALDOC in conjunction with PTGS2 or NR2F1 and found that the combinations had significant prognostic value at the RNA level (Fig. 7 C). Our tissue microarray results,, obtained via immunohistochemistry demonstrated that ALDOC-PTGS2/NR2F1 protein levels predict poor survival and are correlated with tumor grade (Supplementary Tables 2 and 3). This trend was consistent with that observed for RNA and several other clinical cohorts (Fig. 7 D and E). We have also provided Supplementary Tables 4 to further illustrate the potential functions, phenotypes, and pathways associated with ALDOC. In addition, we presented combination treatments with high translational medicinal value. These strategies can serve as guidelines for the treatment of GBM using precision medicine.

The ALDOC-PPARγ axis may have prodgnostic value in gliomas and GBMs. ( A ) Heatmap of the mRNA expression of candidates and various clinicopathological factors in TCGA glioma patients. ( B ) Correlation between ALDOC expression and PTGS2/NR2F1/HTR2B expression in the TCGA GBM cohort. A nonparametric Spearman correlation analysis was used to evaluate the significance of the correlation. ( C ) Kaplan-Meier (KM) analysis of the overall survival in patients with GBM according to ALDOC combined with PTGS2 or NR2F1 expression under various conditions. ( D ) KM analysis of the overall survival rate of patients accordin to ALDOC expression and the combined expression of the PTGS2 protein in three groups of GBM patients (ALDOC high/PTGS2 low, ALDOC low/PTGS2 high, and others) from the GBM TMA cohort. ( E ) KM analysis of overall survival in patients from the GBM TMA cohort according to ALDOC and NR2F1 protein expression at common low (score 0,1) and common high (score 2, 3) levels. The significance of the data was calculated using the log-rank test

Schematic model of the relationship between ALDOC, serotonin and PPARγ signaling in GBM

In this study, we investigated the function of ALDOC in GBM. GBM cell lines were selected by integrating transcriptomic and metabolomic profiles to better predict outcomes. Our results revealed a negative correlation between ALDOC expression levels and hypermethylation status. In addition, we observed a positive association between hypermethylation and increased production of inositol and serotonin. Our model showed that several serotonin (5-HT) receptors were activated, which could promote GBM cell metastasis by increasing serotonin signaling. We used 5-HT antagonists to inhibit signaling and reverse the phenotype, which demonstrates their potential as inhibitors of GBM tumorigenesis. However, serotonin plays a critical role in human physiology and psychology, and the use of 5-HT antagonists can lead to anxiety, depression and other severe side effects. Therefore, we investigated the potential of PPARγ antagonists as alternative therapeutic agents. However, upon evaluation, no significant improvements in cell viability or toxicity were observed, and the antagonists had no effect on body weight in the mouse model. Although previous research has suggested an association between PPARγ antagonists and GBM [ 35 , 36 ], it remains unclear how these antagonists are related to serotonin and ALDOC loss-of-function/hypermethylation events. It is important to note that these options complement the current TMZ treatment and may offer a new combination therapy.

Interestingly, selective serotonin reuptake inhibitors (SSRIs) inhibit serotonin reuptake and increase its concentration in specific brain regions [ 37 ]. Several clinical antidepressants, including escitalopram and fluoxetine, possess this function and are subject to safety regulations. Although their effects may be similar to those of 5-HT inhibitors, antidepressants are associated with significant adverse effects and are clinically restrictive [ 38 ]. In addition, it is necessary to determine whether serotonin production is related to specific 5-HT receptors and investigate the efficiency of reuptake in tissues compared with typical levels.

By combining prior observations with computational analysis, researchers have found that ALDOC expression relies on the apparent modifications in the IDH1 genetic background [ 26 ]. Both low-grade gliomas and GBM, with wild-type and mutated IDH1, showed correlations with various clinicopathological events, and the difference in ALDOC expression was statistically significant on its own. The exact molecular relationship between IDH1 and ALDOC, however, remains uncertain. The affects of the IDH1 gene on hypermethylation of the promoter region of ALDOC or on upstream transcription factor activity may significantly affect ALDOC silencing. Furthermore, due to its pivotal role in the aldolase family, ALDOC is important in connecting glycolysis and the tricarboxylic acid cycle (TCA). Therefore, it is crucial to investigate is the occurrence of a sequence of metabolic reprogramming events and whether GBM tumorigenesis results from 2-HG [ 39 ]. To address these uncertainties, we plan to validate our research findings using IDH1 knockout cell lines or by generating IDH1 R132 mutant cell lines. Our hypothesis is that ALDOC expression induction could serve as an independent factor or as part of a “two-hit” model in combination with IDH1 mutation. This discovery has the potential to advance the use of ALDOC in predicting and diagnosing GBM and other gliomas.

Several datasets focused on the omics of various cancer cell lines have been established. Technical term abbreviations such as omics will be explained when first used. The Cancer Cell Line Encyclopedia (CCLE) project offers well-organized collections of genomic, transcriptomic, proteomic, and metabolomic datasets [ 30 , 40 , 41 ]. In this study, we obtained GBM cell lines and their corresponding bioinformatics backgrounds from the CCLE dataset. Our analysis revealed that serotonin and inositol levels had a considerable effects on the expression of ALDOC and its methylation status. Inositol, also known as vitamin B8 [ 42 ], is an essential vitamin B complex. Scyllo-muco, D-chiro, and neo-inositol are some of the different isomers produced, and they are classified based on their structure [ 43 ]. The most common form is myo-inositol, which is synthesized from glucose 6-phosphate (G6P). Inositol-3-phosphate synthase converts G6P into myo-inositol-1-phosphate, which is then dephosphorylated by inositol monophosphatase to produce the metabolite myo-inositol [ 44 ]. Previous research has demonstrated that inositol is present in certain brain-related disorders [ 45 , 46 ]. To determine the levels of myo-inositol and glutamine or the inositol/creatine ratio in GBM, magnetic resonance spectroscopy is used [ 47 , 48 ]. Additionally, myo-inositol can serve as a biomarker for evaluating the effects of recurrent GBM with or without bevacizumab treatment [ 49 ]. This study contrasts the regulatory impact and metastatic capacity of inositol and serotonin on GBM cells. Furthermore, we supplemented these GBM cell lines with up to 1 mM of myo-inositol. However, our investigation did not reveal any significant changes in metastatic capacity. Nevertheless, the importance of inositol in relation to brain tumors and metabolic processes has been highlighted [ 50 , 51 ]. Additionally, one hypothesis is that ALDOC regulates inositol, which requires further examination and analysis.

This study revealed that a reduction in ALDOC expression and excessive serotonin production lead to GBM phenotypes, such as metastasis, resistance to TMZ and hindered PPAR-γ signaling. The ALDOC/PPAR-γ axis serves as an autonomous prognostic marker. Both in vitro and in vivo experimental results highlight the ability of PPAR-γ agonists to restore the expression of genes associated with these phenotypes and to enhance the clinical impact of TMZ.

STAR ★ Methods

Key resources table, data availability.

No datasets were generated or analysed during the current study.

Abbreviations

2-Hydroxyglutarate

5-Azacitidine

5-Hydroxyindoleacetic acid

Alpha thalassemia/mental retardation syndrome X-linked

Bisulfite sequencing PCR

Cancer Cell Line Encyclopedia

DNA methyltransferase

Epidermal growth factor receptor

Glioblastoma

5-hydroxytryptamine receptor

Isocitrate dehydrogenase 1

Immunohistochemistry

Ingenuity Pahtway Analysis

In ViVo Imaging System

Low Grade Glioma

O6-methylguanine-DNA methyltransferase

Methylation-specific PCR

Nonobese diabetic/severe combined immunodeficiency

nuclear receptor subfamily 2 group F member 1

Selective Serotonin Reuptake Inhibitor

Peroxisome proliferator-activated receptor gamma

Phosphatase and tensin homolog

prpstag; amdom-endoperoxide synthase 2

5-hydroxytryptamine

Tricarboxylic acid cycle

The Cancer Genome Atlas

Temozolomide

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Acknowledgements

We would also like to thank the GRC Instrument Core Facilities for their support for the Affymetrix microarray, IP-MASS spectrometry, IVIS spectrum, and Aperio digital pathology analyses.

This study was supported by Ministry of Science and Technology (MOST-110-2320-B-010-008-MY2), (MOST-111-2314-B-A49-036-MY3), Yen Tjing Ling Medical Foundation (CI-112-6), 113 National Yang Ming Chiao Tung University-Kaohsiung Medical University Joint Research Project (NYCUKMU-113-I0023) and National Yang Ming Chiao Tung University-Higher Education Sprout Project (113W010161).

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Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Yu-Chan Chang & Ming-Hsien Chan

Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei, 235, Taiwan

Chien-Hsiu Li

Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, 110, Taiwan

Chi-Long Chen

Department of Pathology, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan

Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan

Wen-Chiuan Tsai

Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan

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YCC designed and supervised the study and experiments, YCC, MHC, CHL and WCT analyzed the data and co-wrote the manuscript. YCC, MHC, CHL, CLC, MH performed the experiments, analyzed the data, and co-wrote the manuscript. CLC and MH performed histological analysis. WCT provided clinical specimens.

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Correspondence to Yu-Chan Chang .

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Chang, YC., Chan, MH., Li, CH. et al. PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression. Cell Commun Signal 22 , 266 (2024). https://doi.org/10.1186/s12964-024-01645-3

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A doctor stops his brain cancer by undergoing his own treatment

I t’s been a year since Richard Scolyer’s life was turned upside down. The 57-year-old Australian doctor was in Poland when he suddenly suffered a seizure. The diagnosis: glioblastoma, the deadliest type of brain cancer with no cure. Almost twelve months later, Scolyer has managed to stop the progression of the tumor. What happened?

Upon learning about the disease, the doctor underwent an experimental treatment based on his own research on melanoma. Scolyer received immunotherapy designed to cure melanoma before undergoing surgery to remove the tumor. In addition, the doctor received a type of personalized vaccine that increased the effectiveness of the treatment.

A year later, the doctor celebrated the achievement on social media. “I had a brain MRI scan last Thursday looking for recurrent complications of glioblastoma (&/or treatment). I found out yesterday that there is still no sign of recurrence. I couldn’t be happier!!!!! ” he explained on his Twitter account. “Thank you to the fabulous team looking after me so well especially my wife Katie & wonderful family!”

“ People were nervous because it could actually cause my life to end more quickly. But when you’re faced with certain death, it’s a no-brainer for me,” said the University of Sydney professor. He hopes that first-of-its-kind treatment will difference for other cancer patients.

However, it is still early to talk about a complete cure. In addition, the man suffered several side effects during treatment, such as liver difficulties or epileptic seizures .

What is glioblastoma?

According to the Mayo Clinic , glioblastoma is a type of cancer that begins with the development of cells in the brain or spinal cord, in which the cells reproduce rapidly, invading healthy tissues . It develops at any age, but is more common in adult men.

Symptoms of glioblastoma include worsening headaches, nausea and vomiting, blurred or double vision, and seizures. “ There’s no cure for glioblastoma [...] treatments might slow cancer growth and reduce symptoms,” the aforementioned website states.

Treatments to slow the development of glioblastoma typically include surgery to remove it, radiation therapy, chemotherapy, tumor field therapy, targeted therapy, and clinical trials. Scolyer was submitted to the last of them.

Richard Scolyer was diagnosed with glioblastoma, a brain cancer that has no cure. One year later, “there are no signs of recurrence.”

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PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity
Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated ...
Mayo Clinic Minute: Treatment and research of glioblastoma
Glioblastoma is a type of cancer affecting glial cells, which connect nerve cells and support brain function. "It tends to be a tumor that also tends to grow and invade the brain," says Dr ...
A doctor stops his brain cancer by undergoing his own treatment
Treatments to slow the development of glioblastoma typically include surgery to remove it, radiation therapy, chemotherapy, tumor field therapy, targeted therapy, and clinical trials. Scolyer was ...

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Associated Data

The CNS is an immunologically distinct site

Current standard of care and immunotherapy

Immune checkpoint blockade

On the horizon: targeting “next-generation” checkpoints

CAR T therapy

Oncolytic virotherapy

Vaccine therapy

Focused ultrasound therapy

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Acknowledgements

Abbreviations

Availability of data and materials

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The CNS is an immunologically distinct site

Current standard of care and immunotherapy

On the horizon: targeting “next-generation” checkpoints

CAR T therapy

Oncolytic virotherapy

Vaccine therapy

Focused ultrasound therapy

Conclusions and perspectives

Availability of data and materials

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