Generating effective T cell mediated clearance of solid tumors remains an unmet challenge in cancer therapy. Suppressive tumor microenvironments limit the generation of significant numbers of tumor specific T effector cells, their migration to tumor beds, and their subsequent functionality within tumors, thereby blocking the patient’s normally potent acquired immune response from contributing to tumor control.

In an effort to meet this challenge, we have developed novel oncolytic viruses that were bioselected and engineered to cause cancer cell death through two distinct and complementary mechanisms-of-action, direct cancer lysis and tumor-antigen specific T cell generation. Specifically, we have selected and engineered MG1 Maraba virus which both infects tumor tissue to reverse immune suppressive programs while simultaneously delivering vector encoded tumor antigens to the spleen to vaccinate against the patient’s tumor. The result is a large increase in peripheral and tumor infiltrating CD8+ T effectors cells, strong intratumoral inflammatory signatures and ultimately curative efficacy in preclinical solid tumor models. This first-in-class therapeutic strategy is currently being evaluated in Phase 1 and Phase 2 clinical trials.

In this new study, we describe the development of a novel viral immunotherapy platform based on Farmington virus that is: (1) oncolytic in solid tumor models, (2) a potent inducer of highly-functional antigen-specific T cells (expanding tumor specific CD8+ T effector pools over 1000 fold from pre-existing T central memory) and is (3) immunologically distinct from our clinical MG1 Maraba platform. We show that when used sequentially in a heterologous boosting regimen, T cell responses to encoded tumor antigens, either foreign (HPV E7), self (TRP2) or multi-neoantigen, can exceed greater than 50% of all CD8+ T cells in the periphery. The majority of these CD8+ T effectors show markers of polyfunctionality with little expression of the PD-1 exhaustion marker. We will describe our current data assessing the phenotype, localization and potency of these T cell responses in preclinical models of solid tumors and propose strategies to deploy our novel dual oncolytic viral immunotherapy boosting paradigm to the clinic.

Citation Format: David Stojdl. Dual oncolytic viral immunotherapy generates large polyfunctional tumour-specific CD8 + T cell responses that infiltrate immunosuppressive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1473.