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 AdÁAFPÁE1AÁE1B (D55) (AdÁAFPÁD55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/a-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. AdÁAFPÁD55 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 AdÁAFPÁD55. AdÁAFPÁD55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with AdÁAFPÁD55-TRAIL can induce both autophagy owing to the AdÁAFPÁD55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, AdÁAFPÁD55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis.

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