Oncolytic Virotherapy Using the Chimeric Rhabdovirus VSV-GP: Tumor-selective Induction of Cell Death and Immune-Activation

Background: The therapeutic effect of oncolytic virotherapy is largely based on a two-pronged approach - the direct action of tumor-selective infection, viral replication, and cell killing and the associated activation of innate and adaptive immune responses with the potential of long-lasting tumor remission. Using a chimeric vesicular stomatitis virus variant VSV-GP, we addressed the direct oncolytic effects on the syngeneic mouse lung cancer model LLC1 and the activation of an antitumor immune response in the B16 melanoma model. Methods: LLC1 lung cancer tumors and B16 melanoma were established in syngeneic C57bl/6 mice. LLC1 tumors were also grafted in immune-incompetent nu/nu mice. Luciferase expressing VSV-GP was used for live in-vivo imaging to study the quantity and kinetics of virus activity in the tumor. Immune fluorescence histological analysis and FACS analysis were used to assess virus-mediated lysis and immune activation. Results: In vitro, VSV-GP was found to efficiently infect and lyse most cancer cell-lines. Exogenously applied interferon type 1 revealed a dependence of the oncolytic effect on defects in the IFN response of cancer cells. Using a matched pair of LLC1 wildtype and interferon receptor knockout tumors in vivo, interferon insensitivity of cancer cells correlated with prolonged intratumoral viral replication and improved therapeutic outcome. Luciferase imaging also revealed successful tumor-to-tumor spread of viral progeny in bilateral tumor models. Histological analysis revealed widespread and rapid infection and cell killing within the tumor. In contrast, viral replication and tumor-cell killing was limited in the B16-OVA melanoma model, despite showing a therapeutic response in subcutaneous as well as in systemic metastatic settings. FACS analysis revealed an induction of an OVA-specific antitumoral CD8 response as well as an increase of the CD8 to Treg ratio. Conclusions: The direct oncolytic action of VSV-GP correlates with defects in the innate immune defense of tumor cells. On the other hand, VSV-GP can induce an antitumoral immune-response even in tumors with limited permissiveness for prolonged viral replication. Legal entity responsible for the study: Guido Wollmann, Medical University Innsbruck Funding: ViraTherapeutics GmbH Disclosure: G. Wollmann: Part of the presented research was supported by research grants from ViraTherapeutics GmbH and Boehringer Ingelheim via the Christian Doppler Research Foundation. No other financial relationships exist. M. Petersson: Employed by ViraTherapeutics GmbH. D. von Laer: Founder of and serves as Scientific Advisor for ViraTherapeutics GmbH. Minority shareholder of Viratherapeutics GmbH. All other authors have declared no conflicts of interest.