Improving immune recognition of shared tumor-associated antigens in pediatric tumors using a multimodal oncolytic virus

Immunotherapy is an attractive treatment approach for children because of its precision and reduced toxicity. Unfortunately, pediatric solid tumors often evade immune recognition. Like adult cancers, the immunosuppressive tumor microenvironment can restrict immune activity. Further complicating this, pediatric cancers have low mutation rates, creating fewer antigenic targets for the immune response. We therefore developed a multimodal oncolytic virus that harnesses the antiviral immune response and redirects it against shared tumor-associated antigen (TAA) in the tumor. Engineering a TAA, Ephrin A2 (EphA2), into the oncoviral (OV) genome circumvents transcriptional/translational arrest and allows TAA overexpression during infection. Our results show that virus-based EphA2 expression (C57BL/6 sequence) induces an immune-mediated antitumor response in syngeneic C57BL/6-based brain and peripheral tumor models, improving survival (e.g., CT2A brain tumor median survival: 43d-TAA virus vs. 30d-parent virus, 29d-Saline; overall survival: 44.4%-TAA virus vs. 12%-parent virus vs 0%-Saline, *p=0.0233). TAA-virus treatment increases CD8 memory effector-like cells in tumor infiltrates (CD62L+, CD44+) and rechallenge studies show abscopal effect in TAA-virus treated survivors. Peptide pulsing studies using splenocytes from survivors show that viral TAA expression induces a circulating EphA2-specific CD8 effector-like (CD8+, CD25+, Granzyme B+) population (14.1%-TAA virus vs 2.6%-parent virus, 0.6% Saline, **p≤0.0098). This multimodal viral platform harnesses the oncolytic and immunostimulatory properties of a next-generation OV to enhance immune activity against tumors expressing shared tumor antigens. Our results suggest that this flexible viral-based platform provides an effective in situ antitumor vaccination approach and could be engineered against multiple antigens for low mutational load tumors. Citation Format: Mohammed G. Ghonime, Justin C. Roth, Naomi J. Barker, Katherine E. Miller, Elaine R. Mardis, Christopher M. Walker, Kevin A. Cassady. Improving immune recognition of shared tumor-associated antigens in pediatric tumors using a multimodal oncolytic virus [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A15.