Abstract A191: Augmenting the therapeutic efficacy of oncolytic LCMV-GP pseudotyped vesicular stomatitis virus via modulation of the innate immune system

Abstract

Abstract Introduction: Vesicular stomatitis virus (VSV) is a promising oncolytic virus candidate due to its fast mode of action, high titer production, absence of pre-existing anti-VSV immunity and broad tumor tropism. However, potential neurotoxicity of wild-type VSV and a rapid induction of neutralizing antibodies have been a hindrance for further clinical advancement. Our group previously reported that pseudotyping VSV with the LCMV glycoprotein (VSV-GP) results in complete abrogation of neurotoxicity and the absence of neutralizing antibody induction [1]. Here we addressed to what extent the innate immune response to VSV-GP limits its oncolytic efficacy and analyze means to counter these inhibiting factors. Methods: MTT cell viability and TCID50 viral replication assays were used to quantify oncolytic activity in vitro. VSV-GP oncolytic efficiency was also tested in vivo using both xenograft and syngeneic mouse models. Results: VSV-GP exhibited high oncolytic efficiency in vitro, achieving 80-100% killing at 48-72 h post infection in most ovarian, melanoma, and lung cancer cell lines. Further analysis of resistant cell lines showed that these cells were able to mount an interferon (IFN-I) induced antiviral response. VSV-GP efficacy was also tested for ovarian cancer in vivo using s.c xenograft models and in an orthotopic model. Intratumoral injection of VSV-GP into ovarian s.c. xenografts led to tumor remission in all animals. Relapse was observed and relapsing tumors remained sensitive for successive VSV-GP treatment. Significantly prolonged survival was also observed in an ovarian cancer orthotopic model using IVIS in vivo imaging. Oncolytic potency of VSV-GP was enhanced with combination treatment with Jak1/2 inhibitors. Conclusion: These results confirm that LCMV GP-pseudotyped VSV exhibits a highly beneficial toxicity and efficacy profile. However, tumors escaping complete oncolyse via innate immune system activation require coapplication of targeted immune modulators. Reference: [1] - Muik, A. et al. Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency. Cancer Res 74, 3567-3578, (2014). Citation Format: Carles Rodriguez Urbiola, Catherine Dold, Janine Kimpel, Christian Marth, Frederic Santer, Zoran Culig, Alexander Muik, Tanja Knapp, Ira Winkler, Guido Wollmann, Dorothee Von Laer, Patrik Erlmann. Augmenting the therapeutic efficacy of oncolytic LCMV-GP pseudotyped vesicular stomatitis virus via modulation of the innate immune system. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A191.