1. ¹Division of Human Gene Therapy, Department of Medicine, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA
2. ²Department of Obstetrics and Gynecology, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA
3. ³Department of Pathology and Surgery, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Dr JT Douglas, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, BMR2 412, Birmingham, AL 35294, USA. E-mail: jdouglas@uab.edu

Received 17 July 2008; Revised 15 September 2008; Accepted 15 October 2008; Published online 6 February 2009.

Abstract

Conditionally replicating adenoviruses (CRAds) have many advantages as agents for cancer virotherapy and have been safely used in human clinical trials. However, replicating adenoviruses have been limited in their ability to eliminate tumors by oncolysis. Thus, the efficacy of these agents must be improved. To this end, CRAds have been engineered to express therapeutic transgenes that exert antitumor effects independent of direct viral oncolysis. These transgenes can be expressed under native gene control elements, in which case placement within the genome determines the expression profile, or they can be controlled by exogenous promoters. The therapeutic transgenes used to arm replicating adenoviruses can be broadly classified into three groups. There are those that mediate killing of the infected cell, those that modulate the tumor microenvironment and those with immunomodulatory functions. Overall, the studies to date in animal models have shown that arming a CRAd with a rationally chosen therapeutic transgene can improve its antitumor efficacy over that of an unarmed CRAd. However, a number of obstacles must be overcome before the full potential of armed CRAds can be realized in the human clinical context. Hence, strategies are being developed to permit intravenous delivery to disseminated cancer cells, overcome the immune response and enable in vivo monitoring of the biodistribution and activity of armed CRAds.