TY - JOUR T1 - Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2021-002939 VL - 9 IS - 10 SP - e002939 AU - Mohammed G Ghonime AU - Uksha Saini AU - Michael C Kelly AU - Justin C Roth AU - Pin-Yi Wang AU - Chun-Yu Chen AU - Katherine Miller AU - Ilse Hernandez-Aguirre AU - Yeaseul Kim AU - Xiaokui Mo AU - Joseph R Stanek AU - Tim Cripe AU - Elaine Mardis AU - Kevin A Cassady Y1 - 2021/10/01 UR - http://jitc.bmj.com/content/9/10/e002939.abstract N2 - Background Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection.Methods We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice.Results Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations.Conclusions Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.Data sharing not applicable as no datasets generated and/or analyzed for this study. Data are available upon reasonable request. ER -