Effective Strategies for Cancer Gene Therapy using Adenovirus Vectors

Adenovirus vectors (Ads) have been employed for a wide variety of cancer gene therapy applications to date. This utility has derived principally from the unparalleled ability of these agents to accomplish efficient gene delivery to tumor targets. Unfortunately, translation of these advantages has been more difficult to accomplish in human clinical gene therapy trials for cancer. Critical problems to overcome are low efficiency and lack of selectivity of currently available gene transfer systems. In the first instance, it has been recognized that tumor cells manifest a relative deficiency of the primary adenovirus receptor, coxsackievirus and adenovirus receptor (CAR). This CAR deficiency renders tumor cells resistant to Ad thus limiting the therapeutic advantages of this vector. In addition, Ad localizing within the systemic circuit exhibits a marked hepatotropism. Adaptation of Ad for cancer gene therapy applications would thus ideally embody these two mandates-the ability to accomplish CAR-independent gene delivery as a means to improve vector efficiency for tumor targets and the ability to avoid liver sequestration as a means to limit potential vector related toxicity. Herein, we report novel strategies to achieve these goals and thereby improve the utility of Ad for cancer gene therapy applications