702. Concurrent Delivery of GM-CSF and B7-1 Using an Oncolytic Adenovirus Elicits Potent Anti-Tumor Effect on the Growth Established B16-F10 Tumor Model

Abstract

Oncolytic adenoviral vectors are currently being developed as biological anti-cancer therapeutic agents. Coupling the lytic function of oncolytic adenovirus with virus-mediated transgene delivery represents a powerful extension of this methodolgy. To increase the potential anti-tumor activity of oncolytic adenovirus, we constructed an E1B 55kDa deleted oncolytic adenoviral vector, YKL-GB, which expresses both GM-CSF and B7-1. The therapeutic efficacy of YKL-GB adenovirus was evaluated in immunocompetent mice bearing murine melanoma B16-F10 tumors. Significant inhibition of tumor growth was seen in mice treated with YKL-GB compared to those treated with an analogous vector, YKL-1, that lacks GM-CSF and B7-1. Moreover, YKL-GB oncolytic adenovirus demonstrated enhanced anti-tumor activity and a higher incidence of complete tumor regression compared to a replication-incompetent adenovirus, dl-GB, which co-expresses the GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against tumor rechallenge. To establish that anti-tumor effect is associated with the generation of tumor-specific immune response, we examined the cytolytic activity by IFN-|[gamma]| ELISpot assay. We observed that YKL-GB induced significantly higher T cell-mediated antitumor activity than YKL-1. Furthermore, immunohistochemical studies demonstrated robust CD4+ and CD8+ T-cell infiltration in these mice compared to the YKL-1 groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of costimulatory and activation molecules. In conclusion, the findings of this study demonstrate the effectiveness of augmenting the immune response against tumors with oncolytic adenovirus expressing both GM-CSF and B7-1, which provide a potential therapeutic strategy for the management of neoplasia.