Although still considered a rare cancer, glioblastoma (GBM) is the most common malignant primary brain tumor in adults and is one of the most aggressive. The median age at diagnosis is 64 years and, according to the American Cancer Society, the 5-year relative survival rate is just 6% for patients aged 55 to 64 years.

GBM accounts for 54% of all gliomas and 16% of all primary brain tumors.

 The age-adjusted incidence rate is 3.19 per 100,000 persons in the United States. Unlike other malignancies, the disease rate is 2.5 times higher in Whites compared with African Americans; Whites are also more likely to die from GBM.

The few treatments available have demonstrated limited efficacy and survival rate, and advances have barely moved since data supporting the Stupp protocol combining radiotherapy with temozolomide was published in 2005.

 At a median follow-up of 28 months, the combination induced a median overall survival of 14.6 months compared with 12.1 months for radiotherapy alone (HR, 0.63; 95% CI, 0.52-0.75; 

 <.001.) The protocol more than doubled the 2-year OS rate at 26.5% vs 10.4% with radiation.

At least one prominent GBM physician-investigator thinks these outcomes could change soon. Frederick F. Lang Jr, MD, chair of neurosurgery at The University of Texas MD Anderson Cancer Center, and a coleader of the institution’s Glioblastoma Moon Shot program, sees reasons to hope.

“I am optimistic that we are going to see changes in the survival as we start to [better] understand the groups of people we're treating, and as we separate out the tumors more precisely and classify them better,” he said in an interview with 

. “Then, as we understand the biology of [the disease] better and better, we're going to see changes in the near future terms of survival.”

The University of Texas MD Anderson Cancer Center is pursuing several novel approaches, including viro-immunotherapy and genetically engineered natural killer cells to treat patients with GBM, while also conducting tumor analysis to better comprehend the disease.

Historically, Lang said, physicians utilized similar systemic therapies in their patients with GBM as those with other malignancies. However, as more information has been unraveled with brain cancers, researchers have more precisely distinguished between glioblastomas and astrocytomas, tumors that arise from star-shaped cells called astrocytes that make up the supportive tissue of the brain.

Lang said that the ability to precisely classify tumors based on a tumor’s molecular profile, particularly its 

 mutational status, is the biggest advancement in GBM care over the past 5 years.

 wild-type are true glioblastomas and those are a completely different entity from the tumors that are 

 mutant. In the old days, 5 years ago, we used to lump all of those together based on what the pathologist looked at under the microscope. Now we know that those are different tumors. As we become more precise about this, we're going to be applying [our therapies] more specifically to these different tumors—giving us a much more precise outcome.”

Traditionally, investigators have struggled to derive efficacy from immunotherapy in GBM. PD-1 and PD-L1 inhibitors, as well as anti­–CTLA-4 inhibitors, have failed to cross the blood–brain barrier and, as Lang noted, the immune system behaves differently in the brain compared with other organs.

Amy B. Heimberger, MD, the Jean Malnati Miller Professor of Brain Tumor Research and a professor of neurological surgery at Northwestern University’s Feinberg School of Medicine, said GBM tumors are challenging to treat because they are highly heterogeneous and have a high degree of plasticity. Immunotherapeutic agents require an actionable target, the immune system has to be activated, and then the immune system has to traffic to the tumor microenvironment. The immune response then has to stay activated.

“Given the steps that need to take place, you can envision the complexity and deduce that a single agent that just controls one of those factors, that modulates just one of these functions in the setting of immune dysfunction, would not work,” said Heimberger. “In the context of glioblastoma, these are highly immunosuppressive tumors. Even though you might have a target—you may be able to generate an initial immune response—once it gets into that tumor microenvironment, it might not be able to exert the effect of response you desire.”

“With those steps in mind, some of the things I think are a little bit more exciting moving forward for glioblastoma are strategies that activate the immune system used in combination agents that control immunosuppression,” she added.

Earlier this month, AIVITA Biomedical announced findings from a multicenter, phase 2 clinical trial of the personalized cancer vaccine AV-GBM-1 in patients with newly diagnosed glioblastoma (GBM). AV-GBM-1 consists of autologous dendritic cells loaded with autologous tumor neoantigens derived from self-renewing tumor-initiating cells isolated from tumors after routine surgical debulking.

In the study, 57 patients received 8 doses of AV-GBM-1 over 6 months. At the time of the analysis, surviving patients had completed therapy and follow-up ranged from 10.1 months to 27.6 months from enrollment.

Results showed that the median progression-free survival (PFS) was 10.4 months (95% CI, 8.6-11.7) compared with a median PFS of 6.9 months (95% CI, 5.8-8.2) observed in the landmark Stupp trial. Median survival has not been reached and will be assessed after the final patient has a minimum follow-up of 15 months.

In June 2021, the FDA granted Fast Track Designation to VBI-1901, a novel anti-CMV vaccine for the treatment of patients with recurrent GBM with first tumor recurrence. In a small phase 2a trial (NCT03382977), investigators randomized 20 patients to VBI-1901 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) or AS01B. Patients received VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks.

In the GM-CSF arm, the 6-month OS rate was 80% with a 12-month OS of 60%. In the AS01B arm, the 6-month OS rate was 89%, and the 12-month OS rate was not reached.

Heimberger explained that the findings are promising, but cautioned against making too much of either set of data.

“The issue is inadvertent enrollment bias such as a high frequency of patients with 

 mutations that tend to fair better,” she said. “Additionally, did they really get an active T-cell response into the tumor microenvironment? That could also be explored in the context of the window-of-opportunity studies.”

Heimberger, a former co-leader of the Glioblastoma Moon Shot program, was energized about preclinical data published in May. Investigators, including Lang who was a co-author of the study, found that targeting metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) in GBM caused irreversible damage and apoptosis in cancer cells. MCAD breaks down fatty acids that the body can then use for energy.

“This really illustrates a novel therapeutic target,” she said. “I think it's really fascinating. There appears to be a very interesting dependency of the mitochondrial ATP production, specifically in the cancer stem cells, and the cancer stem cells are what gives rise to recurrence and therapeutic radiation resistance.”

Investigators performed a functional genomic screen using patient-derived GBM cells. Results showed that several enzymes involved in fatty acid metabolism were important for GBM cells and focused on MCAD, which was identified in multiple GBM models and found at high levels in GBM cells relative to normal brain tissue.

In-depth studies determined that blocking MCAD in GBM cells resulted in severe mitochondrial failure caused by the toxic buildup of fatty acids. This led to a catastrophic and irreversible cascade of events that resulted in apoptosis in GBM cells.

“The key question that arises is whether this particular mechanism is operational in the vast majority of cells in the tumor microenvironment,” Heimberger concluded. “I think this is a great proof-of-principle study, and certainly, the investigators should really be congratulated because it's a beautiful 

. There are a number of key steps that will be necessary though, in order to get this to a patient.”

American Cancer Society. Survival rates for selected adult brain and spinal cord tumors. Revised May 5, 2020. Accessed June 18, 2021. https://bit.ly/3q6eWhE

Tamimi AF, Juweid M. Epidemiology and outcome of glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 8.doi: 10.15586/codon.glioblastoma.2017.ch8

Stupp R, Mason WP, van den Bent MJ, et al Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 

. 2005;352(10):987-96. doi: 10.1056/NEJMoa043330

AIVITA Biomedical's. AIVITA Biomedical's phase 2 glioblastoma trial shows improved progression free survival. News release. June 8, 2021. Accessed June 18, 2021. https://prn.to/3q9REr7

Wen PY, Reardon DA, Forst DA, et al. Evaluation of GM-CSF and AS01B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM). 

. 2021:39(suppl 15);abstr 2047. doi:10.1200/JCO.2021.39.15_suppl.2047

Puca F, Yu F, Bartolacci C, et al. Medium-chain acyl CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma. 

. Published online May 26, 2021. doi:10.1158/2159-8290.CD-20-1437

Articles

The University of Texas MD Anderson Cancer Center is pursuing several novel approaches, including viro-immunotherapy and genetically engineered natural killer cells to treat patients with glioblastoma, while also conducting tumor analysis to better comprehend the disease. 

Immunotherapy Is on the Rise in Glioblastoma Treatment

Glioblastoma

Amy B. Heimberger, MD, Jean Malnati Miller Professor of Brain Tumor Research, professor of neurological surgery, Feinberg School of Medicine, Northwestern Medicine, discusses the variability of responses in glioblastoma.

Some efficacy signals have been observed with immunotherapy in glioblastoma, says Heimberger. However, it is important to note that survival varies in this disease with some patients benefitting significantly more or less than median projections, Heimberger explains. 

Research efforts have shown that some genetic features could be predictive of survival in patients with glioblastoma, says Heimberger. For example, 

 mutations, which are typically expressed in low-grade gliomas, are present in a subset of glioblastoma, Heimberger says. Patients with stage IV glioblastoma who harbor 

 mutations appear to have improved survival compared with patients who lack the mutation, Heimberger explains. As such, clinical trials in glioblastoma should account for these genetic features to interpret how patients respond to certain therapeutic approaches, concludes Heimberger.

Videos

Amy B. Heimberger, MD, discusses the variability of responses in glioblastoma.  



Dr. Heimberger on the Variability of Responses in Glioblastoma 

Stephanie E. Weiss, MD, FASTRO, chief, Division of Neurologic Oncology, professor, Department of Radiation Oncology, director, Radiation Oncology Residency and Fellowship Training Program, Fox Chase Cancer Center, central nervous system cancers panel member, National Comprehensive Cancer Network, discusses selecting optimal radiation therapy for patients with brain metastases.

How to best sequence treatment for patients with brain metastases is an area of ongoing research, says Weiss. Regarding radiation therapy, two options are available for this patient population, Weiss explains.

Whole brain radiation therapy can help prevent new lesions from forming, but the modality is associated with toxicities, such as significant fatigue and neurocognitive changes, Weiss says. Stereotactic radiosurgery, which is being increasingly utilized for patients with brain metastases, treats individual lesions vs treating the entire brain, concludes Weiss. 

Stephanie E. Weiss, MD, FASTRO, discusses selecting optimal radiation therapy for patients with brain metastases.  



Glioblastoma

Articles

Immunotherapy Is on the Rise in Glioblastoma Treatment

Videos

Dr. Heimberger on the Variability of Responses in Glioblastoma

Dr. Weiss on Selecting Optimal Radiation Therapy for Brain Metastases