Genetically Engineered Natural Killer Cells: A Novel Approach to Treating Glioblastoma

This content originally appeared on our sister site, OncLive.

Glioblastoma (GBM), while still considered a rare cancer, is the most common malignant primary brain tumor in adults, accounting for 54% of all gliomas and 16% of all primary brain tumors. GBM is one of the most aggressive cancers - the median age of diagnosis is 64 years and the 5-year relative survival rate in patients afed 55 to 64 years is just 6%, according to the American Cancer Society.^1,2

The age-adjusted incidence rate of GBM is 3.19 per 100,000 persons in the United States, and unlike other malignancies, the disease rate is 2.5 times higher in White patients compared with African American patients. White patients 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 2005.3 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; P <.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 OncLive. “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 IDH mutational status, is the biggest advancement in GBM care over the past 5 years.

“Tumors that are IDH wild-type are true glioblastomas and those are a completely different entity from the tumors that are IDH 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.”

Vaccines Point the Way Forward

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.⁴

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.⁵

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 IDH 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.⁶

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

References

1. 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
2.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
3. Stupp R, Mason WP, van den Bent MJ, et al Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. doi: 10.1056/NEJMoa043330
4. 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
5. 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). J Clin Oncol. 2021:39(suppl 15);abstr 2047. doi:10.1200/JCO.2021.39.15_suppl.2047
6. Puca F, Yu F, Bartolacci C, et al. Medium-chain acyl CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma. Cancer Discov. Published online May 26, 2021. doi:10.1158/2159-8290.CD-20-1437