Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-[beta]

Genetic immunotherapy is considered an ideal treatment modality for cancer because of its systemic nature. This study was designed to develop a potent novel genetic immunotherapy by combining conditionally replicating adenovirus (CRAd) and replication-defective adenovirus expressing interferon-[beta] (ad-IFN-[beta]). We investigated the efficacy of this therapy in an immunocompetent mouse tumor model. Transduction with CRAd ([DELTA]24RGD) induced cytolysis in a mouse lung cancer cell line (Lewis lung carcinoma (LLC)). Combined transduction of ad-IFN-[beta] and [DELTA]24RGD in the LLC cells induced a greater and more prolonged production of IFN-[beta]. Media transfer from the LLC-[DELTA]24RGD-ad-IFN- [beta] to untransduced LLC cells induced the production of IFN-[beta]; these results confirmed the replication and release of ad-IFN-[beta]. LLC cells transduced with ad-IFN-[beta] and [DELTA]24RGD had decreased tumorigenicity in syngeneic mice. Tumor vaccination with irradiated LLC-ad-IFN-[beta]-[DELTA]24RGD showed a significant increase in the survival of tumor-bearing syngeneic mice compared with mice with a single transduced LLC vaccination; this was mediated by an enhanced cytotoxic T-lymphocyte response against the LLC cells. The results of this study showed that cotransduced [DELTA]24RGD to ad-IFN-[beta] aided the replication of ad-IFN-[beta] in the LLC cells. A high local concentration of IFN-[beta] and local release of tumor antigen by CRAd induced strong antitumor immunity. This combination strategy might provide a powerful means by which ad-cytokines and CRAd can be combined and other adenoviruses expressing different cytokines might also be used. Cancer Gene Therapy (2010) 17, 356-364; doi: 10.1038/cgt.2009.78; published online 6 November 2009 Keywords: conditionally replicating adenovirus; adenovirus-IFN-[beta]; lung cancer; genetic immunotherapy