Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

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Abstract
We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3–interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-α. We hypothesized that the anticancer efficacy of the KD3–IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON–SEAP vector was obtained. Coinfection with TetON–TRAIL augmented oncolytic activity of KD3 and KD3–IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON–TRAIL and KD3–IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-α-mediated immunotherapy, and pharmacologically controlled TRAIL activity.