850. 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

Coupling the lytic function of an oncolytic adenovirus with its ability as a transgene delivery system represents a powerful extension of this methodology. A clear advantage is the amplification of a therapeutic gene, as replicating vectors would be able to infect and deliver the gene of interest to neighboring cells. To increase the anti-tumor effect of an oncolytic adenovirus, we have generated an E1B 55kDa deleted oncolytic adenoviral vector, YKL-GB that 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 the analogous vector, YKL-1. Moreover, YKL-GB oncolytic adenovirus demonstrated enhanced anti-tumor activity and higher incidences of tumor regression compared to a replication-incompetent adenovirus, dl-GB, which co-expresses GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against a tumor re-challenge. To establish that the observed anti- tumor effect is associated with the generation of a tumor-specific immune response, we examined the cytolytic activity using an IFN-γ ELISpot assay. We observed that YKL-GB induced significantly higher T cell-mediated anti-tumor activity than YKL-1. Furthermore, immunohistochemical studies demonstrated robust DCs and CD4+/ CD8+ T-cell infiltration in these mice compared to the YKL-1-treated groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of the co-stimulatory and activation molecules. These findings demonstrate the effectiveness of enhancing the immune response against tumors with an oncolytic adenovirus expressing both GM-CSF and B7-1 and provide a potential therapeutic strategy for the management of neoplasia.