Gene therapy that causes the urinary bladder to secrete interferon-alpha shows great promise in animal trials, even with human cell lines normally resistant to the protein, according to an article in the September issue of Molecular Therapy.

The researchers said their findings are very promising for treating aggressive human superficial bladder cancer and a clinical trial is being planned.

In the current work, 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 interferon-alpha.

"Of course these results have been achieved in mice, not humans, but they are very exciting," said lead author William Benedict, MD. "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, use of the BCG (tuberculosis) vaccine, tumors reappear in about half of patients, and up to 30 percent of them will die from disease.

Because neither BCG vaccine nor chemotherapy can effectively prevent a significant percentage of superficial bladder cancer tumors from becoming aggressive, researchers had been studying novel gene therapy for this clinical problem.

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., to evaluate recombinant adenoviruses encoding interferon-alpha. The modified adenoviruses can produce high levels of interferon-alpha when they infect cells, but are engineered to prevent virus replication. The investigators combined the interferon-alpha gene with an additional agent, Syn3, to enhance expression of interferon in the cells lining 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, incorporated the interferon-alpha gene, 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," said Benedict. "In addition, there was little apparent toxicity."

One of the key advances was 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 added. "That has never been seen before."

"The degree of effectiveness of the Ad-IFN_/Syn3 therapy was a surprise to all of us," concluded 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."