OTME-16. Polio virotherapy of murine brain tumors causes microglia/macrophage proliferation and inflammation that is potentiated by immune checkpoint blockade

Abstract

PVSRIPO is a novel viral immunotherapy that has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in 21% survival rate at 36 months following treatment. To improve clinical response rate, it is critical to resolve the mechanisms of action and therapy resistance in vivo, thereby designing effective combination therapy strategies.We used immunocompetent mouse models of glioma (CT2A) and metastatic melanoma (B16) to dissect early and late events following virotherapy with PVSRIPO. A blinded systematic review of the pathology from 62 intracranial tumors, collected on different days following PVSRIPO (or control) treatment, was performed. An overall treatment effect, measured by tumor shrinkage, dis-cohesive growth pattern, microglia enrichment, was present in 88% of tumors on day 8, but the tissue response rate fell to 42% on days 10 & 12, and 14% on day 15. The control group showed no treatment effect throughout. RNAseq from the same set of samples showed acute induction of type-I interferon-related inflammation that faded with time in Gene Set Enrichment Analysis. This suggests that sustaining adaptive antitumor immunity elicited by immediate intratumor type-I IFN-dominant inflammation is critical to long term remission. Careful review of the post treatment pathology revealed an early enrichment of both T cells and microglia in the tumor microenvironment with a high Ki-67 proliferation index. We propose that the PVSRIPO therapy effect is dependent on macrophage/microglia mediated cellular immune response, likely in response to direct viral infection. This suggests potential therapeutic interventions, including blockade of the PD1:PD-L1 immune checkpoint, to potentiate antitumor CD8+T cells in response to PVSRIPO therapy. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed higher long term remission (37%, n=11), compared to either monotherapy; this effect is CD8+T cell- and macrophage-dependent, demonstrated by depletion studies in vivo.