Data from Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector

Abstract

<div>Abstract<p>An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (<i>a</i>) the high infectivity of adenoviruses for hepatic cells, (<i>b</i>) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (<i>c</i>) tumor selectivity provided by α-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing <i>murine interleukin-12</i> (<i>mIL-12</i>) genes or reporter gene <i>LacZ</i> showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both <i>in vitro</i> and in an <i>in vivo</i> hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying <i>mIL-12</i> gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy. (Cancer Res 2006; 66(3): 1620-9)</p></div>