Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated Ad.AFP.E1A.E1B (Delta 55) (Ad.AFP.D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/alpha-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. Ad.AFP.D55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into Ad.AFP.D55. Ad.AFP.D55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with Ad.AFP.D55-TRAIL can induce both autophagy owing to the Ad.AFP.D55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, Ad.AFP.D55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis. Gene Therapy (2011) 18, 765-777; doi:10.1038/gt.2011.16; published online 17 March 2011