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Monday, March 2, 1998
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Synthetic Peptide Vaccine for Melanoma Holds Promise

Early clinical trials of a synthetic vaccine are showing promise in obtaining an immune response from patients with melanoma, an often-deadly form of skin cancer, according to researchers at the National Cancer Institute (NCI). NCI investigators designed a peptide that mimics the antigen that sits on the surface of a patient's own tumor cells. This peptide was then used to vaccinate patients and evoke an immune response.

The study demonstrates that it is possible to get the immune system to recognize a protein or antigen that is present on a melanoma cell. "This is an essential research step in developing new immunotherapies for the treatment of patients with cancer," said Steven A. Rosenberg, M.D., Ph.D., chief of surgery at NCI and the principal investigator.

Results of the study involving 31 patients whose melanomas had spread (metastasized) to other sites in the body were published in the March issue of Nature Medicine.

All of the patients received a vaccine mixture containing the designer peptide (of the antigen gp 100) and an oil-based adjuvant to enhance its uptake by the immune system. In addition, the patients were given interleukin-2, a growth factor isolated from T-lymphocytes, white blood cells that orchestrate the immune response. After two to four vaccine injections every three weeks, 13 patients (42 percent) receiving the vaccine and IL2 combination exhibited a 50 percent or greater tumor shrinkage at all sites. In previous studies, this compared to tumor shrinkage in only 17 percent of patients receiving IL-2 alone.

In their Nature Medicine article, Rosenberg and his colleagues cautioned, however, that this apparent difference in response rates must be demonstrated in a randomized clinical trial evaluating the peptide vaccine in combination with IL-2. Such trials involving large numbers of patients are now being planned at several university centers in the United States, according to Rosenberg.

At the time of publication, he said, the longest duration of response seen with the vaccine/IL-2 combination was six or seven months, although since then, several patients continue to be disease-free.

A majority of patients in the study were between the ages of 31 and 60 and had advanced disease. All of the patients were heavily pretreated with surgery and in some cases, patients had also undergone prior chemotherapy, radiotherapy, or immunotherapy including IL-2.

Rosenberg said that the peptide chosen for the vaccine was the most potent of a handful of peptide derivatives of the gp100 antigen -- one of two major antigens that he and his co-researchers have identified that elicit natural immunity against melanoma. Both proteins are effective antigens only in individuals expressing HLA-A2, a common immune system marker that enables the immune system to distinguish between "self" and non-self in launching an immune response. Because this marker is so common, it is anticipated that vaccines incorporating gp100 could have widespread use in patients with melanoma.

Identifying tumor-associated antigens has long been a major goal of cancer vaccine research. Melanoma has been a particular target of such research, both because the advanced disease is so difficult to treat, and because it seems to be unusually responsive to immunologic changes.

In 1985, Rosenberg and his colleagues discovered that immune stimulation with interleukin-2 could mediate cancer regression. Three years later, they discovered that certain immune cells found in tumors have potent activity against the tumors from which they derive. Known as tumor-infiltrating lymphocytes (TIL), these cells are able to destroy the tumor cells, and have provided Rosenberg's team and others with a valuable tool for identifying tumor antigens in melanoma and other cancers, as well as the genes that encode them. This ability, in turn, has opened up new strategies for treating patients using their own immune systems (immunotherapy) to attack cancer.

The present study, Rosenberg said, shows that it is possible to stimulate a vigorous immune response even when patients have a heavy tumor burden. Work is in progress, he added, to develop similar strategies to treat other cancers such as ovarian, breast, and prostate cancer.

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*The study is titled, "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma." The authors are S.A. Rosenberg, J.C. Yang, D.J. Schwartzentruber, P. Hwu, F.M. Marincola, S.L. Topalian, N.P. Restifo, M.E. Dudley, S.L. Schwarz, P.J. Spiess, J.R. Wunderlich, M.R. Parkhurst, Y. Kawakami, C.A. Seipp, J.H. Einhorn, and D.E. White. Nature Medicine,Vol. 4, No. 3, March 1998.