Gene delivery from replication-selective viruses: arming guided missiles in the war against cancer

Gene therapy aims to deliver therapeutic genetic material in a safe and efficient manner to a target tissue, where it can accumulate to levels that afford maximal patient benefit. Replication-defective viral vectors have been the workhorse of gene therapy for cancer and other conditions. These vectors allow the efficient delivery of a variety of transgenes to target tissues and have demonstrated clear therapeutic benefit and safety in a variety of preclinical neoplastic animal models. Unfortunately, the tremendous promise of studies using replication-defective viruses in preclinical models has not been translated into similar patient benefits in the clinical setting (1–3). This shortfall may be due in large part to the one-dimensional nature of these approaches, asking for a successful therapeutic outcome against a highly complex biological target like a human tumor through the activity of a single gene. Therapeutic gene delivery needs to develop into a multidimensional system if it is to be successful in treating human cancers. A natural evolution of gene therapy is its incorporation into replication-selective oncolytic viruses, combining the antitumor properties of the viral infection with the action of the therapeutic proteins.