T-cell pose mystery in skin cancer patients

Advanced melanoma, the deadliest form of skin cancer, can be treated successfully by vaccinating patients with tumor proteins - but this therapy does not work consistently. A group of researchers is attempting to solve this medical mystery.

In two recent articles published in the Journal of Experimental Medicine, Pierre Coulie, M.D., Ph.D., and Thierry Boon, Ph.D., professors at the Catholic University of Louvain, Brussels, Belgium, and their associates explain that these vaccines work by increasing the number of immune cells - known as killer T-cells - that can attack a malignant tumor. An unexpected result of their research, however, indicates that these cells mostly recognize tumor proteins that were not contained in the vaccine. A deeper understanding of the characteristics of T-cell populations that are expanded after vaccination may lead to the development of more widely effective anti-tumor vaccines.

MAGE-3 antigen Dr. Coulie's and Dr. Boon's groups studied anti-tumor T-cells in patients vaccinated with an antigen called MAGE-3. They observed tumor regression in about 20 percent of the metastatic melanoma patients who received MAGE antigen-based vaccines. The mechanisms of tumor regression, however, do not appear to be those that the group expected.

According to Dr. Coulie, examination of the tumor environment showed that high levels of anti-tumor CTLs, formed naturally by the body prior to vaccination, could be largely responsible for the regression. Somehow, the MAGE vaccine altered the tumor environment in a way that the previously ineffective, naturally occurring anti-tumor CTLs were now helping to dissipate the tumor. The vaccine, then, seemed to serve as a welcome side effect, reinvigorated previously dormant tumor-specific immune cells, and also seemed to spawn new anti-tumor CTL.

Looking for a trigger Dr. Coulie and his group are now working to understand how the vaccine triggers the immune intervention of the previously powerless lymphocytes. His current hypothesis is that the few T-cells stimulated by the vaccine may change the local, suppressive environment of the tumor to the extent that other existing T-cells become aggressive and vigorously attack the tumor.

"Vaccination of cancer patients with tumor-specific antigens recognized by T lymphocytes is aimed at producing a response of anti-tumor T lymphocytes capable of attacking the tumor cells," Dr. Coulie says. "It was previously thought that a massive number of these anti-tumor T lymphocytes would have to be produced to ensure elimination of the large number of tumor cells present in a tumor. Our results strongly suggest an alternative scenario."

He says melanoma tumors appear to be loaded with ineffective - or, as he puts it, "paralyzed" - anti-tumor T-cells before vaccination. These T-cells probably reflect a failed attempt of the patient's immune system to eliminate the tumor.

"Following vaccination, the T-cells directed against the vaccine antigen are present in low number, but they are capable of attacking some tumor cells in one location," Dr. Coulie says. "This reverses locally the immunosuppressive environment and reawakens the anti-tumor T-cell response of the patient, thereby generating a massive number of anti-tumor T-cells that are directed at tumor antigens other than those present in the vaccine."