Identifying Rational Immunotherapy Combinations for Glioblastoma: A Progress Report

Leading global experts believe that for immunotherapy to work in glioblastoma (GBM)—which has an estimated 5-year survival rate of 33% in the United States—combination treatments are the way forward. This was the most important takeaway from one of the sessions that kicked off the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Chairing the session was Amy B. Heimberger, MD, professor, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center. During her presentation, Heimberger provided the audience with a flavor for potential strategies that can be tapped to induce antitumor immune-induction in glioblastoma.

“What are key steps necessary for an optimal antitumor immune therapeutic response in brain tumors?” she asked, considering that glioblastomas are highly immunosuppressive.

How do we overcome lack of T-cell infiltration in the tumor? She shared the results of a successful single patient strategy in a patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR) T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple intracranial infusions of the IL13Rα2 CAR T cells in the resected tumor cavity, as well as in the ventricular system, resulted in a regression of intracranial and spinal tumors in that patient—a response that was sustained for 7.5 months.¹

The CAR domain has several limitations, Heimberger pointed out: the lack of tumor-specific antigens, antigen escape, and in vivo persistence and generation of a product in a timely fashion.

“All these limitations need to be addressed to view the efficacy of CAR T cells in GBM," she said.

Her laboratory has developed a small molecule inhibitor against STAT3—another key driver of GBMs. The researchers developed a small-molecule inhibitor called WP1066, which, they found, can block M2 macrophages. The drug has minimal toxicity, but it is lipophilic, meaning it is difficult for the drug to dissolve in the blood stream. The team had to be innovative in its approach: the researchers spray-dried the drug with methocellulose. A phase 1 trial of WP1066 is ongoing in patients with GBM refractory to treatment.

Another approach to treating GBM is via viral vaccines, and Michael Platten, MD, Mannheim University Hospital, German Cancer Research Center, provided the audience with an overview of where the field stands.

His team has developed a novel method to detect the immunological presentation of the mutated antigen in tumor tissue of brain tumor patients.

“We don’t know what the relevance of whole tumor vaccines is,” Platten said, and explained that several unknowns remain, including:

• How do you select appropriate target antigens?
• What are the appropriate biomarkers?
• How do you bring the vaccine in context with immunotherapeutics/checkpoint blockade agents?

There are 3 categories of antigens in GBMs, he noted:

• Tumor-associated antigens: shared antigens; have low immunogenicity and potential for side effects
• Viral antigens: usually not endogenous; heterogenous if exogenously expressed
• Tumor antigen: specific but not a strong immune response.

A recent paper published by Liau et al evaluated the impact of adding an autologous tumor lysate-pulsed dendritic cell vaccine to standard therapy in new GBM. The randomized phase 3 trial showed median overall survival of 34.7 months from surgery; 3-year survival was 46.4%.²

Platten said that there is growing understanding in the field for neoepitope vaccines; these are unique to tumor cells and most epitopes arise from single nucleotide variables. Most neoepitopes are private with the majority being class II epitopes. Gliomas have about 30 to 100 nonsynonymous mutations per megabase. Shared neoepitopes include EGFRvIII and IDH1R132H receptors.

“Clonality remains a question with shared epitope vaccines,” he said, adding that the natural clonal evolution of GBM results in the acquisition and loss of subclonal neoepitopes.

Platten believes the following treatments can complement vaccines in GBM treatment:

• Immunosuppressive agents for the tumor microenvironment
• Radiation therapy and oncolytic viruses
• Immune checkpoint blockade agents
• Small molecule targets

Immune response monitoring remains a significant issue in GBM treatment. “We need better tools to capture patient response to treatment,” said Platten.

Gavin P. Dunn, MD, PhD, Washington University School of Medicine in St. Louis, was up next. He provided an update on checkpoint inhibitors and combination strategy with targeted immunotherapies in GBM. Current checkpoint inhibitors do not have any indication for GBM.

While there are some responders to immunotherapies, presenting with long-term control and partial remission after pseudoprogression, the question is, how do you identify these responders? “While there are anatomic site-specific considerations, the checkpoint pathway does remain the canonical pathway for targeting T-cell immune responses,” Dunn said.

Studies have shown a trend of increased sensitivity to checkpoint blockade with increasing mutational burden for different cancer types, he said. “Therefore, mutation burden is the engine for generating candidate neoantigens.”

While some studies have shown that the incidence of hypermutated genotype in primary GBMs is low, research from his lab has shown that hypermutated patients with GBM do respond to PD-1 inhibitors—in this case, pembrolizumab.³

However, researchers need to be aware of the failure nodes of immune function, which can lead to lack of response to checkpoint blockade in GBM:

• Lack of efficient antigen presentation
• Impaired homing mechanisms
• STAT reactivation at the tumor site
• Checkpoint inhibition blockade inhibition or T-cell exhaustion

Dunn noted that there are 4 ongoing trials that are evaluating rational combination treatments for recurrent GBM, including the CAPTIVE trial and another evaluating a LAG3 inhibitor or urelumab in combination with nivolumab.

Dunn agreed with previous speakers that combination therapy may be the way forward for the successful treatment of GBMs.

References

1. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561-2569. doi: 10.1056/NEJMoa1610497.
2. Liau LM, Ashkan K, Tran DD, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. doi: 10.1186/s12967-018-1507-6.
3. Johanns TM, Miller CA, Dorward IG, et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 2016;6(11):1230-1236.