Diphtheria toxin and immune factor fight melanoma

A drug containing parts of the diphtheria toxin appears to prompt the immune system to recognize and kill cancer cells in patients with advanced skin cancer, a team of researchers at UofL's James Graham Brown Cancer Center has discovered.

Preliminary results of a phase II clinical trial, presented Nov. 9 at an international symposium in Prague, Czech Republic, showed that five out of seven human patients with stage IV melanoma experienced significant regression or stabilization of both tumors and the spread of cancer.

Jason Chesney, M.D., Ph.D., associate director for translational research at the Brown Cancer Center and an assistant professor of medicine at the University of Louisville School of Medicine, presented one of only 10 projects at the conference, which was sponsored by the European Organization for Research and Treatment of Cancer, the National Cancer Institute and the American Association for Cancer Research.

His was selected from almost 800 peer-reviewed research presentations.

"The immune system that attacks cancer cells in humans depends on a balance between T-cells, which recognize and attack tumor cells, and suppressive or regulatory T-cells, which turn off activated immune cells in order to prevent autoimmune disease," Chesney said.

In research with mice, Chesney's team discovered that the drug denileukin diftitox targets and depletes regulatory T-cells, allowing particular T-cells in the immune system known as CD8 + T lymphocytes to attack and kill the melanoma cells.

This success led to testing of the drug in human patients.

Chesney and his colleagues gave seven patients with stage IV melanoma 9 or 12 micrograms of the drug per kilogram of body weight daily for four days, every three weeks for four cycles. Five patients who received the higher dose experienced significant regression of several metastatic tumors.

All of the patients are still alive after 12 months, and the phase II trial is continuing to examine the effectiveness of the drug, Chesney said at a news briefing. Stage IV melanoma patients normally have a median life expectancy of about eight months.

"To our knowledge, this is the only trial to study the effects of regulatory T-cell depletion in human cancer patients," he said.

"The results demonstrate that depleting these cells in patients with melanoma may allow the immune system to activate and successfully kill cancer cells. These patients have survived longer than the median average life expectancy of a patient with stage IV melanoma.

"We believe that, in the future, this approach to therapy may prove to be useful in all types of cancer."