538. Fiber Chimeric Oncolytic Adenoviral Vectors Mediate Efficient Gene Transfer and Oncolysis of Head and Neck Cancer and Melanoma Cells In Vitro and In Vivo

Abstract

Listen

Translate article

Current treatment modalities for melanoma and head and neck cancers (HNC) are not completely effective and there is an urgent need for development of novel therapeutic strategies. Oncolytic adenoviruses (OAVs) designed to selectively replicate and kill cancer cells are rapidly emerging as promising agents for oncolytic virotherapy. However, low expression levels of the adenovirus receptors, CAR and integrins in melanoma and HNC cells have imposed significant hurdles to the use of adenovirus type 5 (Ad5)-based vectors. To improve gene transfer and mediate efficient oncolysis of these cells, fiber chimeric vectors in which the fiber knob was replaced with the fiber knob domain of Ad35 were generated. Marker gene expression mediated by the fiber chimeric vectors in melanoma and HNC cell lines was approximately 10-fold higher than that obtained with parental Ad5 virus. The fiber chimeric structure was then built into an oncolytic adenovirus, in which the expression of the E1a gene is placed under the control of E2F-1 promoter. The cytotoxicity mediated by fiber chimeric vectors in melanoma and HNC cells was 100-fold better than that mediated by the parental Ad5 vector. In addition, the fiber chimeric structures improved the virus yields as much as 100-fold in several melanoma and HNC cells. These results correlated with low levels of CAR and high levels of CD46 on the surface of the cancer cell lines. The results of in vitro transduction, cytotoxicity and virus yields assays correlated with the results of in vivo anti-tumor efficacy studies in FaDu xenograft tumor model in nude mice. These findings have important implications for the potential treatment of melanoma and HNC using fiber chimeric oncolytic adenovirus.