In addition to the tumor shrinkage that occurred in some of the patients in the clinical trial, the treatment also induced evidence of autoimmunity - signs that the immune system was attacking not only patients' tumors, but also normal tissue. With treatment, physicians were able to completely eliminate all symptoms of autoimmunity that occurred in the trial.

"There are two important findings from this study," said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI and the lead researcher on the study. "First, we are able to shrink tumors by including CTLA-4 inhibition as a component of immunotherapy. Additionally, the autoimmune effects seen in six of the patients in the study demonstrate that under normal circumstances, CTLA-4 plays a critical role in preventing the immune system from destroying the body's own healthy tissue."

CTLA-4 is one of many molecules that control the activation of T cells, specialized immune cells that recognize and kill foreign cells that have invaded the body. When CTLA-4 is turned on, it interferes with T cell activation, abating the immune response. Researchers hoped that by preventing activation of CTLA-4 they could enhance T cells' ability to recognize and attack tumors in the body.

The 14 patients in the study received an antibody that blocks CTLA-4 activity, plus a cancer vaccine made up of a small segment of a protein found on the surface of melanoma cells. Although it is hoped that the vaccine will stimulate the immune system to attack cancer cells, in previous clinical trials, this type of vaccine alone was insufficient to cause melanoma tumors to shrink. Researchers speculated that CTLA-4's inhibition of T cell activity might be in part responsible for this lack of an effective immune response.

Blocking CTLA-4 did indeed improve the response to treatment. In two of the patients in the study, all tumors, which included significant metastases in the lung and brain, disappeared completely. A partial response, defined as a 30 to 100 percent decrease in tumor size, was seen in one additional patient. In another two patients, some tumors decreased in size, but other tumors continued to grow.

Six patients, including all of those whose tumors regressed, experienced significant autoimmune effects in normal tissues in response to the treatment. The enhanced activity of immune cells in these patients led to symptoms including skin rashes, inflammation of the colon, and hepatitis. With treatment, all of these symptoms were resolved.

In order to attack foreign cells that have invaded the body while maintaining tolerance for the body's own tissues, the immune system is kept in check by a complex balance of signals. "What we found in this study is that when you unleash immune cells' activity against the tumor, you also unleash their ability to destroy normal tissue," Rosenberg said. "Fortunately, we were able to completely eliminate all these effects by treating with steroids."

Researchers hope that with further studies it may be possible to dissociate autoimmune effects against tumors from those against normal tissue. However, these symptoms may be necessary, treatable side effects of immunotherapy for cancer, Rosenberg said.

* Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockage in patients with metastatic melanoma. Proc Natl Acad Sci 2003. Published the week of June 23 - 27, 2003, in PNAS Online Early Edition, http://www.pnas.org.

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