Oncolytic VSV Primes Differential Responses to Immuno-oncology Therapy.

ABSTRACT: Vesicular stomatitis virus encoding the IFN? transgene (VSV-IFN?) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFN?. Here, we show that VSV-IFN? exhibits multiple mechanisms of action, including direct cell killing, stimulation of an innate immune response, recruitment of CD8 T cells, and depletion of T regulatory cells. Moreover, VSV-IFN? promotes the establishment of a CD8 T cell response to endogenous tumor antigens. Our data demonstrate a significant enhancement of anti-tumor function for VSV-IFN? when combined with checkpoint inhibitors, but not OX40 agonists. While the addition of checkpoint inhibitors to VSV-IFN? generated robust tumor growth inhibition, it resulted in no increase in viral replication, transgene expression, or immunophenotypic changes beyond treatment with VSV-IFN? alone. We hypothesize that tumor-specific T cells generated by VSV-IFN? retain activity due to a lack of immune exhaustion when checkpoint inhibitors were used.

SUBMITTER: Durham NM 

PROVIDER: S-EPMC5542805 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature