Novel Approach to Interferon-Alpha Gene Therapy for Bladder Cancer in a Mouse Model

Abstract

Gene therapy that causes the bladder to act like a "bioreactor" to produce and secrete the anti-cancer agent interferon-alpha has shown dramatic benefits in preclinical tests, say researchers at The University of Texas M. D. Anderson Cancer Center.The researchers say their findings, published in the September issue of Molecular Therapy, suggest this gene therapy strategy holds much promise for treating aggressive human superficial bladder cancer and that a clinical trial is being planned.Human bladder tumors growing in experimental mice substantially decreased in size after two treatments with novel gene-based therapy. There was little or no evidence of cancer cells remaining in the bladder in many of the mice after treatment. Also, every kind of bladder cancer cell line tested in the laboratory responded, even cells known to be resistant to the interferon-alpha protein."Of course these results have been achieved in mice, not humans, but they are very exciting," says the lead investigator William Benedict, M.D., professor in the Department of Genitourinary Medical Oncology. "I have never seen a potential therapy for superficial bladder cancer that could produce such marked regression of tumors within the bladder."Bladder cancer is the fifth leading U.S. cancer, and "superficial" bladder cancer -- cancer confined to the lining of the bladder wall -- is the most common type, with more than 45,000 new cases each year. Although some patients with this cancer can be cured with the standard biologic therapy, the use of BCG, tumors will reappear in about half of patients, and up to 30 percent of them will die from disease. Because neither BCG nor chemotherapy can effectively prevent a significant percentage of superficial bladder cancer from becoming aggressive, researchers at M. D. Anderson have been studying novel gene therapy approaches to this clinical problem. Their work is being funded by a $13 million Specialized Programs of Research Excellence (SPORE) grant awarded to M. D. Anderson by the National Cancer Institute in 2001 ¯ the only such federal SPORE dedicated to bladder research.The bladder has long been thought to be ideal target for gene therapy, because it is easily accessible by catheter, and is largely a self-contained "bag-like" organ. Benedict and his team of researchers decided to look at use of gene therapy to deliver interferon-alpha, an immune system modulator which can improve a patient's natural response against cancer as well as kill cancer cells directly. Interferon-alpha is commonly used as treatment in a number of cancers, such as several types of leukemias, lymphoma, melanoma, and kidney cancer. However, it has been observed that tumor cells can become resistant to the immune protein.To investigate alternative ways to deliver interferon, the researchers teamed up with scientists from the San Diego biotechnology company Canji, Inc., which is affiliated with Schering-Plough Corporation, to evaluate recombinant adenoviruses encoding interferon-alpha. These modified adenoviruses can produce high levels of interferon-alpha when they infect cells, but are engineered to prevent virus replication. The investigators combined recombinant adenoviruses encoding interferon-alpha with an additional agent, Syn3, to enhance expression of IFN in the cells which line the inside of the bladder.Mice that were growing human tumors in their bladders received two one-hour instillations directly into the bladder. The cells lining the inside of the bladder, both normal and cancerous, "took up" the recombinant adenoviruses encoding interferon-alpha, and a marked decrease in tumor size was seen. "This is a major finding since many human bladder cancer cell lines are resistant to the interferon-alpha protein, including the ones used in this study," says Benedict. "In addition, there was little apparent toxicity."One of the key advances is that the virus was able to harness cells in the bladder to function as "biological factories, producing high local concentrations of interferon-alpha in the bladder over an extended time," he says. "That has never been seen before.""The degree of effectiveness of the recombinant adenoviruses encoding interferon-alpha/Syn3 therapy was a surprise to all of us," says Benedict. "We know that going from mouse to man is a crucial step, but if the therapy performs half as well in the clinic as in this preclinical study, we may well significantly advance the care of patients with bladder cancer."Working with Benedict on the study was, from Canji, Inc.: Robert Connor, Ph.D., Jennifer Philopena, Heidrun Engler, D.V.M., Ph.D., William Demers, Ph.D., and Daniel Maneval, Ph.D.; and from M. D. Anderson: Ziming Tao, M.D., Chang-Soo Kim, M.D., Xinqiao Zhang, Ph.D., Jain-Hua Zhou, M.D., Ph.D., Liana Adam, M.D., Ph.D., David McConkey, Ph.D., Angela Papageorgiou, Mark Munsell, and Colin Dinney, M.D.