Characterizing oncolytic potential and safety of a G-protein pseudotyped vesiculovirus in sarcoma

Abstract

Abstract Several vesicular stomatitis virus (VSV)-based oncolytic therapies have advanced to phase II clinical trials for treatment of solid tumors. As most antibodies produced after VSV infection are directed towards the surface glycoprotein (G), switching this G-protein of VSV to that of a novel virus could enable repeat dosing in cancer patients by evading adaptive immunity. We aim to study whether a hybrid virus expressing the G-protein of a closely related and non-pathogenic vesiculovirus exhibited oncolytic efficacy across sarcoma models. We compared cytotoxic effect of VSV, VX1 (wild-type novel virus), and VxG (hybrid) post infection in sarcoma lines. We quantified viral progeny production over time and compared real-time rate of viral-induced apoptosis. Sarcoma lines were tested for production of type-I interferon (IFN) and protection from VxG-induced cell death by exogenous IFNβ. We completed in vivo efficacy studies of intratumoral administration of VxG in xenograft and syngeneic models. From syngeneic tumors, we performed immunophenotyping on residual tumors treated with VxG compared to controls. VxG was observed to be well tolerated and efficacious. In a xenograft model, a single low-dose administration of VxG completely inhibited tumor growth compared to controls. Lower tumor burden was observed in syngeneic tumors treated with VxG compared to controls. Comparisons of tumor infiltrating lymphocytes between residual VxG treated and control tumors will be completed. We conclude that the novel hybrid virus VxG has potent oncolytic effects in multiple models of sarcoma and low toxicity in immunocompetent mice. Future endeavors will focus on improved viral engineering and further pre-clinical studies. Supported by the Mayo Clinic Graduate School of Biomedical Sciences