Abstract 4193: Lymphotoxin-alpha-armed oncolytic VSV-GP synergizes with SMAC mimetics to induce enhanced tumor cell death and regression

Abstract

Abstract Introduction: Oncolytic viruses (OVs), which selectively replicate in and destroy tumor cells, form a highly promising class of cancer therapeutics with a strong immune stimulatory potential. VSV-GP, a chimeric Vesicular Stomatitis Virus (VSV) pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (LCMV) can selectively replicate and express therapeutic cargos in the tumor microenvironment. Lymphotoxin alpha (LTα) - a member of the TNF superfamily - may present as a potent therapeutic cargo based on its immune stimulatory and cell death modulatory characteristics.In this study, we explore the immune promoting and tumor cell death inducing properties of VSV-GP-LTα, a next generation variant with an NF-κB facilitated mode of action. We further investigate clinically relevant combination therapies with “second mitochondria-derived activator of caspases” mimetic compounds (SMCs). Experimental Procedures: Viral fitness, cargo expression and test substance quality were assessed using growth kinetic, ELISA, RT-qPCR and titration assays. Therapeutic efficacy and safety of VSV-GP-LTα, with or without SMC co-treatment, were assessed in vivo in syngeneic C57BL/6 mice bearing subcutaneous LLC1-IFNAR-/- or B16F10-OVA tumors. To shed further light into the VSV-GP-LTα treatment effects, we applied immunohistochemistry, flow cytometry, multiplex ELISA and Nanostring® assays. Data Summary: VSV-GP-LTα induced stronger anti-tumor effects and increased overall survival compared to VSV-GP. It was also better tolerated than VSV-GP armed with TNF-α, a therapeutic cargo from the same class. Histological and gene expression analysis confirmed widespread cell killing within the tumor and activation of innate and adaptive immune response markers. However, further characterization of the adaptive immune compartment did not show significant changes induced by the expressed LTα. Building on the observed therapeutic strengths of VSV-GP-LTα, we further explored a treatment combination with SMC. This resulted in a therapeutic synergy with improved treatment-induced tumor cell death, especially in a less permissive tumor setting. Conclusion: Together, here we show that arming VSV-GP with LTα resulted in a strong inflammation of the tumor microenvironment and enhanced levels of tumor cell death induction. This effect could be further enhanced by the co-treatment with SMC. Citation Format: Bart Spiesschaert, Philipp Müller, Katharina Angerer, Krishna Das, Tobias Nolden, Carles Urbiola, Judy Ng, Fabian Heinemann, Birgit Stierstorfer, Patrik Erlmann, Guido Wollmann. Lymphotoxin-alpha-armed oncolytic VSV-GP synergizes with SMAC mimetics to induce enhanced tumor cell death and regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4193.