TMOD-17. ONCOLYTIC POLIOVIRUS AS A PROBE FOR MECHANISMS OF IMMUNE RESISTANCE IN GLIOBLASTOMA

Abstract

Abstract Glioblastoma is an immunologically cold tumor that employs multiple resistance mechanisms to escape activation of both innate and adaptive immunity. Transient immune activation and responses induced by immunotherapies in glioblastoma are almost always suppressed by potent intrinsic and extrinsic resistance mechanisms, limiting therapeutic efficacy. PVSRIPO is a recombinant poliovirus/rhinovirus chimera that elicits robust innate immune activation through infecting and lysing glioblastoma cells expressing the human poliovirus receptor (CD155), and through sublethal infection of tumor associated macrophages, setting the stage for lingering viral replication. We have constructed a pathological model using murine CT2ACD155 intracranial tumors stereotactically infused with a single dose of PVSRIPO (5×107 pfu) or mock control to study the response of glioblastoma in an immune competent in vivo tumor microenvironment. Tumor bearing brains were harvested before therapy and on days 2, 4, 6, 9, 12 post therapy for histology. On day 4 post therapy, histopathology showed > 90% shrinkage of intracranial tumor diameter (n= 6/6). Residual tumor is surrounded by a necrotic rim on histology with profound infiltration of F4/80+ macrophages and substantially reduced expression of Ki-67 on IHC compared to controls. Other markers including CD3, CD8 and Cleaved-Caspase 3 showed no difference in tumors of both groups. Interestingly, most residual tumor progressed on day 6 post therapy and caught up with the size of control tumor by day 9. Long-term remission of tumor occurred in only 10% of mice. This model is valuable in studying the mechanisms of intrinsic resistance and the timeline of resistance to develop in order to obtain more durable immunotherapy responses in glioblastoma. Future steps are to track inflammation induced by viral infection by RNAseq, and to find potential therapeutic interventions (including blocking PD1:PD-L1 axis) to mitigate therapy resistance in this preclinical model.