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Identifying Rational Immunotherapy Combinations for Glioblastoma: A Progress Report

Surabhi Dangi-Garimella, PhD
Leading global experts believe that for immunotherapy to work in glioblastoma—which has an estimated 5-year survival rate of 33% in the United States—combination treatments are the way forward.

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.


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