Melanoma may not be the commonest form of skin cancer but it is surely the nastiest, being unresponsive to chemotherapy or radiotherapy. Most texts will tell you, simply, that early diagnosis followed by surgery is the only therapeutic option. In general, clinically useful cancer vaccines, used here in a treatment rather than in preventive sense, have proved elusive. Might melanoma provide an exception? Dr. Steven Rosenberg and colleagues from the U.S. National Cancer Institute, Bethesda, Maryland, certainly hope so, for this has been one of the group's main areas of activity for some time. Many others are on the trail. The U.S. National Library of Medicine's website, when accessed on August 9th, 1999, revealed 190 papers on melanoma vaccine in the past two years. The latest review so found concluded that immunotherapy with melanoma vaccine was better than conventional treatment (see J.M. McGee et al., South. Med. J., 92:698-704, 1999).

   That review also noted a trend towards refining the tumor antigens for these vaccines. For example, in one 1999 paper, on a "unique" melanoma antigen recognized by tumor-infiltrating cells, Rosenberg's group describe a mutated triosephosphate isomerase with T-cell stimulating activity vastly greater than that of the wild (normal) type (see R. Pieper, et al., J. Exp. Med., 189:757-66, 1999). In their highly cited Nature Medicine paper at #4, Rosenberg et al. used a previously identified melanoma antigen modified by replacing a threonine by a methionine at position 2, thus achieving greater binding to recognition molecule HLA-A2 and increased production of melanoma-reactive cytotoxic T lymphocytes. The laboratory data confirmed that patients could be immunized with this synthetic peptide vaccine—but what of the clinical evidence?

   Early clinical studies of experimental therapies in cancer do tend to be in patients with advanced disease, and the 51 chosen by Rosenberg's team had extensive metastatic disease and had already received several treatments previously. When the modified antigen (known as g209-2M) was used together with interleukin-2, a response rate of 42% was recorded.

   In paper #2, the approach of Frank O. Nestle and colleagues from Switzerland and Germany to the question of how to improve the "presentation" of antigens was different. They used the dendritic cell, which is a rare form of lymphocyte, exposed to a "cocktail" of melanoma antigens or to tumor lysate. In the 16 patients—again, all had metastases and earlier treatment failures—Nestle et al. recorded three complete responses and two partial responses. The injections were given directly into the lymph nodes. Two of the responders had been given the tumor lysates—i.e., the relevant tumor antigens were not identified, in contrast to the more tailored precision of the Rosenberg strategy.

   Commenting from Stanford University Medical School's Division of Oncology, California, John M. Timmerman and Ronald Levy note that vaccination with free peptide can be a "double-edged sword....altering the dosage can result in tolerance rather than protective immunity." (see Nature Medicine, 4:269-70, 1998).