IMMU-37. PRE-TREATMENT INNATE INFLAMMATION ASSOCIATES WITH SURVIVAL AFTER POLIO VIROTHERAPY AND CAN BE MODULATED TO SENSITIZE GLIOMAS TO IN SITU VACCINATION

Abstract

Abstract Early-stage clinical trials in glioblastoma (GBM) have tested various virotherapy strategies, yet only a subset of patients appear to benefit. We previously demonstrated that a recombinant poliovirus (PVSRIPO) functions by inducing MDA5-dependent, type I interferon (IFN) dominant innate inflammation in myeloid cells to provoke durable and functional antitumor T cell responses in mice. Long-term survival after intratumoral PVSRIPO infusion was observed in a subset of patients with recurrent GBM (rGBM) in two clinical trials. Survival after PVSRIPO was associated with higher pre-treatment intratumoral neutrophil density and MHC-class II gene expression, but also higher pre-treatment inflammatory cytokines in blood. Post-treatment induction of type I/III IFNs detected in blood one day after PVSRIPO infusion also associated with survival of patients with rGBM, suggesting that the proficiency of IFN responses to PVSRIPO may dictate therapy outcome. In human ex vivo glioma tissue assays, only a subset of gliomas mounted type I IFN responses to PVSRIPO and STING agonist treatment, in a manner linked with higher pre-treatment IL-1b levels, and lower CXCL10 induction after treatment. Thus, baseline innate inflammation either influences or reflects the capacity of glioma tumors to respond to virotherapy. Strikingly, in glioma bearing mice, peripheral vaccination against tumor irrelevant vaccines in alum adjuvant (i.e., against antigens not expressed by the tumor) induced bone marrow, spleen and intratumoral innate inflammation; rescued the antitumor efficacy of PVSRIPO in an otherwise refractory glioma model; and improved survival after intratumor STING agonist therapy. Notably, peripheral vaccination induced intratumoral neutrophil and CD4+ T cell inflammation, and increased MHC-class II expression on myeloid cells. These data imply a role for pre-treatment systemic innate immune training in the antitumor efficacy of virotherapy and indicate that modulating either systemic innate inflammation and/or the inflammatory status of bone marrow myeloid progenitors may sensitize gliomas to virotherapy.