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Recent success using immunotherapies to treat a growing range of cancer types has reinvigorated efforts to identify effective immune-based treatments for glioblastoma (GBM). However, the limited clinical benefit observed in GBM patients treated with checkpoint blockade immunotherapy (CBI) has indicated a need for more rigorous approaches to augment host-immune recognition and killing of GBM. Of the myriad barriers to effective brain tumor immunotherapy, one potentially critical consideration is that a more systematic approach to tumor-specific antigen identification and targeting is necessary to potently stimulate and direct T cells to treat GBM. Therefore, in this study we set out to identify endogenous tumor neoantigens in the anti-PD-L1 resistant murine glioblastoma, CT2A, and assess the efficacy of neoantigen vaccination in combination with anti-PD-L1 treatment. In order to identify candidate CT2A neoantigens, we employed DNA whole exome sequencing, RNA sequencing, and in silico neoantigen prediction analyses. High-affinity H-2Kb and H-2Db candidate CT2A neoantigens were screened for immunogenicity by IFN-γ ELISPOT assays. Of the 30 top-ranking neoantigen candidates, 13 demonstrated immunogenic CD8+ T cell responses in the spleens of mice vaccinated with mutant peptides. Assessing for endogenous reactivity, we identified neoantigen specific CD8+ T cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted, Epb4H471L and Pomgnt1R497L, and one H2-Db restricted neoantigen, Plin2G332R. Survival studies showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with anti-PD-L1 checkpoint blockade was superior to either neoantigen vaccination or anti-PD-L1 therapy alone. Thus, by applying a cancer immunogenomics approach to identify endogenous neoantigen reactivity in an aggressive and treatment resistant murine glioblastoma, we provide a preclinical framework to investigate the effects of multi-modality immunotherapeutic interventions in anti-glioma immunity.

neuro-oncology

IMMU-09. COMBINATION IMMUNE TREATMENT OF A HIGHLY AGGRESSIVE ORTHOTOPIC MURINE GLIOBLASTOMA WITH CHECKPOINT BLOCKADE AND MULTI-VALENT NEOANTIGEN VACCINATION