Innate Antiviral Signals for Cancer Immunotherapy

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Glioblastomas (GBM) feature a profoundly immunosuppressive myeloid infiltrate that constitutes a formidable barrier to therapy. The infiltrate’s cellular composition, and the tissue context provided by specialized resident myeloid cells in the CNS (microglia), distinguish GBM from other malignancies. The principal mediators of immunosuppression in the tumor microenvironment (TME), glioma-associated macrophages/microglia (GAMM), are exceedingly difficult therapy targets. Their entrenched immune subversive traits, phenotypic heterogeneity and plasticity pose obstacles to targeted GAMM re-polarization. The goal of this project is to decipher the mechanisms of GBM immunotherapy with recombinant poliovirus, PVSRIPO, a neurotropic +strand RNA virus with a deep pro-inflammatory imprint. Poliovirus naturally targets the mononuclear phagocytic system— macrophages, microglia, dendritic cells (DC)—due to constitutive expression of its receptor CD155 in this compartment. Wild type poliovirus infection is lytic in DCs/macrophages. In contrast, PVSRIPO, engineered for attenuation by internal ribosomal entry site (IRES) exchange with human rhinovirus type 2, has a peculiar non- cytopathogenic host relationship defined by accentuated innate antiviral signaling. Infection of the glioma TME with PVSRIPO unleashes multilayered proinflammatory events, including lingering +strand RNA virus replication within GAMM, activation of diverse innate signaling cascades via multiple double-stranded RNA sensors, profuse type-I interferon dominant inflammation, polio-specific CD4+T cell immunologic recall in the tumor, and widespread microglia activation and proliferation in the normal brain. PVSRIPO has shown promise with single intratumor administration in recurrent GBM, yielding durable radiographic responses associated with long-term survival in a subset of patients. We uncovered that patients whose tumors had relatively lower mutational burden and who experienced a short time to 1st recurrence survived longer after PVSRIPO. These features were associated with enhanced TME inflammatory signatures, indicating that tumor-intrinsic conditions for GAMM engagement influence immunotherapy outcomes. Our central premise is that PVSRIPO generates glioma immune surveillance via proinflammatory activation of GAMM resulting in stimulation of local tumor antigen cross-presentation, T cell infiltration of brain parenchyma, and enhanced CD8+T cell effector functions. Realizing this potential in the clinic for all patients depends on resolving mechanisms that govern antitumor CD8+T cell immunity in the brain. To achieve this objective, we propose the following Specific Aims: (1) Determine the mechanisms of microglia/GAMM proinflammatory activation induced by recombinant poliovirus; (2) Elucidate the impact of microglia cross-presentation on PVSRIPO immunotherapy; (3) Determine if repeat dosing or CD40 ligation improve the antitumor efficacy of PVSRIPO.