Delivery systems intended for in vivo gene therapy of cancer: Targeting and replication competent viral vectors

Cancer gene therapy represents one of the most rapidly evolving areas in pre-clinical and clinical cancer research. Application of gene transfer techniques in clinical trials has made increasingly obvious that several issues will need to be addressed prior to meaningful incorporation of gene therapy in the care of cancer patients. Two of the most important problems to overcome are lack of selectivity of the existing vectors and low efficiency of gene transfer. This review focuses on use of targeting and replication competent vectors in order to overcome these obstacles. Targeted gene therapy of malignancies can be achieved through vector targeting or transcriptional targeting and can improve the therapeutic index of gene transfer by preventing damage of normal tissues, an important requirement if systemic gene delivery is contemplated. Replication competent viral vectors can improve the efficiency of gene transfer. Provisionally replicating viruses can also improve the therapeutic index by targeting toxicity to tumor cells. A variety of provisionally replicating viruses, such as the attenuated adenovirus ONYX-015, the adenovirus CN706 that selectively replicates in prostate cancer cells, the double mutant herpes simplex virus G207, the human reovirus, and the Newcastle disease virus are currently in clinical trials. Early clinical results and limitations in the application of these vectors are discussed.