A new preclinical study evaluating the potential of using Advexin, Introgen's adenoviral p53 cancer therapeutic, is an anti-cancer vaccine strategy. The study was published in the March 15, 2002 issue of 'Gene Therapy.'

The preclinical study is designed to evaluate safety and therapeutic response in tumor-bearing mice immunized with Advexin treated dendritic cells. Results of this study showed that Advexin therapy induces a potent antitumor immune response in vivo and that there is no evidence of toxicity or autoimmune complications.

Jack A. Roth, M.D., chair of the Department of Thoracic and Cardiovascular Surgery at The University of Texas M. D. Anderson Cancer Center, and an author of the manuscript said, "This study demonstrates for the first time that p53 can function as a safe and effective activator for the immune system to target cancer cells. Importantly, this study expands the therapeutic applications of Advexin; this drug may be used to kill cancer cells directly, and may also stimulate the immune system to attack additional tumor cells."

Almost 50 percent of cancer cells in humans accumulate the p53 protein as a result of mutations in the p53 gene. This accumulation provides a target for cancer immunotherapy. Two previous collaborative studies with Dmitry Gabrilovich, M.D. of the H. Lee Moffitt Cancer Center at the University of South Florida, provide the basis for evaluating the potential of p53 immunotherapy. One study showed that Advexin adenoviral-p53 acts as an immunogen in stimulating human immune cells to selectively kill cancer cells over-expressing the p53 gene. A separate study demonstrated that immunization with Advexin-activated dendritic cells could slow the growth of and block new development of tumors.

This new study was designed to expand upon the previous results and to specifically address safety issues related to this novel form of immunotherapy. In this study, mice were immunized with dendritic cells treated with an adenoviral vector encoding the mouse p53 gene. As before, p53 served as a potent tumor antigen and 60 percent of treated animals were protected against tumor development. When the dendritic cells were activated, 100 percent protection against tumors was achieved. Importantly, no evidence of autoimmunity was seen in these immunized animals.

"Not only does p53 serve to direct the immune system to kill cancer cells, once the immune system has eliminated tumor cells over-expressing p53, there is no evidence of toxicity. This suggests that this approach can be tested clinically in cancer patients with the goal of developing a cancer vaccine to treat existing tumors and prevent new tumor growth," commented Sunil Chada, Ph.D., director of research and development at Introgen, and an author of the manuscript.

Dr. Gabrilovich, principal author said, "It was necessary to demonstrate safety of this strategy prior to designing studies to evaluate this new immunization strategy in cancer patients. Now that we have overcome this final test, by combining the potent cancer cell killing activity of Advexin with an immunotherapeutic strategy, we will evaluate moving this therapy forward into the clinic."

"Development timelines of Advexin as a cancer vaccine may be shorter because issues such as manufacturing, safety and biodistribution have been resolved in the twenty clinical trials already conducted by Introgen. Human safety has been evaluated in numerous routes of administration, including intratumoral, intracranial, intraperitoneally, and direct repeated intravenous infusion," said Max W. Talbott, Ph.D., Introgen's senior vice president of worldwide commercial development.

Introgen has developed Good Manufacturing Practices (GMP) compliant production capabilities and expertise via the production of the worldwide phase 2 and 3 requirements of Advexin over the past five years. Based on this expertise, the company was awarded the production contract for the adenoviral reference material by the Williamsburg BioProcessing Foundation, acting as facilitator for the Adenoviral Reference Material Working Group. Academia, industry and worldwide regulatory bodies will use this reference standard as a standard for the development of adenoviral gene therapy products. The Office of Cellular and Gene Therapies of the U.S. Food and Drug Administration advised on the award. In addition, Introgen currently has agreements for manufacturing and process development in place with select third parties.

Advexin is a patented cancer therapeutic incorporating the p53 tumor suppressor gene in an adenoviral delivery system. Advexin is designed to use the p53 gene to kill cancer cells and to stop tumor growth, without harming normal cells, in cancer patients with both normal and damaged p53 genes. The p53 gene interferes with cancer cells because it is a tumor suppressor gene and carries instructions to make a protein that reacts with the damaged DNA of a cancer cell. Specifically, the p53 protein activates one of two pathways in these cells, to either stop growth by "hibernating" the cell or induce death via a process of programmed cell death, called apoptosis. Both processes provide an important brake to the development of certain cancers.