Abstract
Abstract Oncolytic viruses (OV) that preferentially replicate in and kill tumor cells are promissing novel treatment option for advanced cancers. Through cell lysis, OV set tumor antigens free, which in combination with the OV adjuvant effect, unleashes a strong anti-tumor immune response. Here, we propose the use of the oncolytic VSV-GP for the treatment of ovarian cancer. Effective oncolytic activity of VSV-GP could be demonstrated in a panel of ovarian cancer cell lines. Analysis of the innate immune response of ovarian cancer cells to VSV-GP revealed IFN type I production and induction of an antiviral state of the cells as a potential mechanism leading to shortcomings in virotherapeutic treatment. In vivo, VSV-GP was tested in a subcutaneous ovarian cancer xenograft mouse model using the A2780 cell line. Treatment led to tumor remission, which was temporary in most mice resulting in tumor recurrance. In an orthotopic xenograft mouse model, intraperitoneal injection of the virus led to significantly prolonged survival compared to untreated animals. In addition, combination therapy of VSV-GP with the JAK1/2-inhibitor ruxolitinib was successfully tested in both models and found to enhance the oncolytic effect. The drug inhibited the signalling pathway induced by type I IFN and could thus be used to inhibit the antiviral innate immune response and enhance intratumoral viral replication. Importantly, despite inhibiting the antiviral response, no toxicity was observed in mice receiving up to 109 pfus (plaque forming units) VSV-GP via intraperitoneal application. In addition, using luciferase expressing VSV-GP, we found no off target tropism with ruxolitinib combination. In conclusion, VSV-GP was tested as a potent oncolytic virus to treat ovarian cancer. Restriction of viral replication due to the innate immune response could be overcome by the combination treatment of VSV-GP with the Jak-1/2 inhibitor ruxolitinib. Citation Format: Janine Kimpel, Carles R. Urbiola, Catherine Dold, Christian Marth, Alexander Muik, Dorothee Holm-von Laer, Guido Wollmann. Innate immunity modulators to enhance oncolytic VSV-GP for the treatment of ovarian cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B114.
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