Trans‐complementing adenoviral vectors for oncolytic therapy of malignant melanoma

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Abstract
Background Despite attempts to develop efficient viral‐based gene transfer therapies for the treatment of malignant tumors, only limited progress has been made to improve the efficacy of this approach. As an alternative, the use of replicating oncolytic adenoviruses with and without the expression of therapeutic transgenes is an area of active investigation. Methods We used a human melanoma xenograft tumor nude mouse model to test the efficacy of a bivalent vector approach consisting of two trans‐complementing replication‐incompetent adenoviral vectors that resulted in tumor‐restricted oncolysis. We combined an E1‐deleted non‐replicating adenoviral vector expressing the herpes simplex virus thymidine kinase gene (AV.C2.TK) and Ad5.dl1014, an E4‐deleted/E4orf4‐only expressing adenovirus, to allow full replication competence when tumor cells were co‐infected with both vectors. Results A375 tumors showed apoptosis at the ultrastructural level after transduction with the trans‐complementing vector system that was not seen with injection of either vector alone. Apoptotic DNA fragments could be co‐localized to sites of infection with the adenoviral vectors. A significant survival benefit was achieved for the trans‐complementing vector treated animals compared to animals treated with either vector alone. Interestingly, the administration of GCV did not further increase animal survival over treatment with the trans‐complementing system of viruses alone, and long‐term survival was only seen in the trans‐complementing vector treatment group. Intraperitoneal administration of a pseudo‐wild‐type vector Ad.dl327 resulted in significant hepatotoxicity, while intraperitoneal administration of the trans‐complementing vectors resulted in only mild liver abnormalities. Conclusions The trans‐complementing vector approach using a combination of E1‐ and E4‐deleted adenoviral vectors showed similar antitumor efficacy as reported for monovalent replicating vector systems, but may offer additional safety by reducing the risk of dissemination of the replication‐competent vectors by requiring the presence of both vectors in a cell to achieve replication competence. Copyright © 2004 John Wiley & Sons, Ltd.