Neoadjuvant systemic oncolytic vesicular stomatitis virus is safe and may enhance long-term survivorship in dogs with naturally occurring osteosarcoma

Abstract

VSV-IFNβ-NIS is a recombinant oncolytic vesicular stomatitis virus (VSV) that is being evaluated clinically for the treatment of advanced malignancies. As with other cancer immunotherapies, identifying biomarkers of response will be critical to the clinical advancement of this treatment approach. Here we describe the first evaluation of neoadjuvant intravenous oncolytic VSV therapy in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs, a disease with similar natural history as its human counterpart. VSV-IFNβ-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors pre- and post-treatment. Alterations in the tumor microenvironment (micronecrosis, fibrosis, and inflammation) were more pronounced in VSV-treated dogs than in placebo-treated dogs. A 'tail' of seven long-term survivors (35%) was apparent in the VSV-treated group. RNAseq analysis showed that virtually all the long-term responders had increased expression of a CD8 T-cell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFNβ-NIS has an excellent safety profile and may provide a survival benefit for dogs with osteosarcoma whose tumors are permissive for immune infiltration. These data support ongoing translation of neoadjuvant VSV-IFNβ-NIS to human cancer patients. Strategies to further enhance clinical benefit include dose escalation or combination with other immunomodulatory agents.