Innovative Approaches for Enhancing Cancer Gene Therapy

P.B. Fisher
Virginia Commonwealth University, US

Keywords: cancer, gene therapy, adenovirus

Summary:

In principle, gene therapy using viruses that selectively replicate in cancer cells and simultaneously produce a second cancer-toxic gene product should provide precise and effective approaches for cancer therapy. Unfortunately, although active in cells in culture and in pre-clinical models, lacking an intact immune system, this strategy has not proven as effective as anticipated in clinical trials. This raises the question of what hurdles need to be overcome to make gene therapy of cancer an efficacious strategy for treating both primary tumors and metastases. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hindered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major impediments for effective gene therapy using Ads include the restricted infectivity of wild type Ad serotype 5 (Ad5), the most commonly used Ad for gene therapy, and the inability to specifically deliver the therapeutic directly into diseased tissue, trapping in the liver and/or elimination by the immune system. Restrictions in tumor delivery using wild type Ad5 result from reductions in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by using tropism-modified Ads that permit CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now also be overcome by using a novel targeted-delivery approach employing ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD) resulting in target site-specific therapy in immune competent transgenic mouse models. Using UTMD combined with a Cancer Terminator Virus (CTV), a virus that displays cancer-selective replication and produces a therapeutic systemically active cytokine (such as mda-7/IL-24), enhances the ability to treat both primary tumors and metastases. These unique strategies for boosting the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing selective and effective gene therapies of cancer.