Abstract 4313: Preclinical safety and efficacy of VSV-IFN-b in a syngeneic, immunocompetent model of head and neck squamous cell carcinoma

Abstract

Abstract Objective& Background: VSV, an RNA virus of the rhabdoviridae family, induces potent cytolytic effects in immortalized cells and cells with defects pathways of IFN or PKR in vitro & in vivo. To take advantage of defects in IFN response in tumors, and to improve the virus’ therapeutic window, “second generation” VSVs expressing IFN-b were developed and characterized (Obuchi et. al. 2003). The aims of this study are to evaluate the effects of VSV-IFN-b in human and rodent head & neck cancer cell lines and to assess the safety and in vivo antitumor efficacy of VSV-IFN-b in syngeneic rat head & neck cancer models. Methods: Rat (FAT-7) and mouse (SCC VII) squamous cell carcinoma cells were infected in vitro with VSV-rat-IFN-b and VSV-mouse -IFN-b. Viruses were propagated using the BHK-21 cells according to established protocols. ELISA & Western blotting were performed to identify the expression of rat-IFN-b post infection, in SCC-VII & FAT-7 cells, respectively. Viral cytotoxicity during normoxia and hypoxia, viral replication and IFN-b expression were assessed to determine sensitivity of rat and mouse SCC cells to VSV-IFN-b. An in vivo model of rat squamous cell carcinoma was established by injection of 3×106/ml of FAT-7 cells SC on the floor of the mouth in immunocompetent female Fisher-344 rats. VSV-rat-IFN-b was administered intratumorally at different doses and schedules when tumors reached a diameter of 70-100 mm3. Antitumor efficacy and toxicity were evaluated during the study. Results: VSV-IFN-b induced significant cytotoxicity and successfully propagated in FAT-7 and SCC VII during normoxia and hypoxia. IFN-b production was increased at 24 and 48 hours after viral infection. Rat SCC cells were more susceptible to VSV-rat-IFN-b than mouse cells, and the cytotoxic effects were similar to VSV-human IFN b on rat cells. Tumors were successfully induced and were palpable at 21 days after inoculation. IT administration of VSV-rat-IFN-b resulted in reduction in tumor size and improved survival compared to the non-treated controls. The antitumor effects of one dose of the virus at 5×108 pfu was more effective than higher doses (5×109) or repeated doses. IV administration of a single dose of VSV-rat-IFN-b (5×108) exerted similar antitumor effects as IT administration. No signs of acute toxicity were observed in treated rats after single or repeated IT or IV virus administration. Conclusion: VSV-IFN-b induces cytotoxicity in FAT-7 and SCC-VII cancer cells during normoxia and hypoxia. In vivo, VSV-rat-IFN-b was associated with antitumor effects and prolongation of survival compared to untreated controls. Characterization of viremia, tissue biodistribution, in vivo viral replication and gene expression in vivo are underway in preparation for future clinical evaluation of VSV-human-IFN-b in subjects with advanced head and neck cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4313. doi:10.1158/1538-7445.AM2011-4313