Synthetic Peptide Melanoma Vaccine

For this article, Eugene Russo interviewed Steven A. Rosenberg, chief of surgery at the National Cancer Institute. Data from the Web of Science (ISI, Philadelphia) show that this paper has been cited significantly more often than the average paper of the same type and age. 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, D.E. White, "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma," Nature Medicine, 4:321-7, March 1998. (Cited in more than 170 papers since publication) This paper translated years of molecular data on the immune system into tangible human clinical trial results. National Cancer Institute chief of surgery Steven A. Rosenberg and his colleagues had been trying to develop new cancer immunotherapies for more than 15 years by attempting to understand the molecular basis of patients' responses to their own cancers. This paper "represents one of the first approaches in which rationally designed cancer vaccines could reproducibly raise immune reaction against spontaneous cancers in humans," says Rosenberg, who's one of the most highly cited oncologists of all time according to the Institute for Scientific Information in Philadelphia. "It represents an application of this burgeoning information about the molecular nature of the immune reaction against cancer." A 1988 study by the group suggested that some patients' cancer will regress when treated with tumor-infiltrating lymphocytes plus the cytokine interleukin-2.1 Steven A. Rosenberg In hopes of finding the key to tumor regression, Rosenberg's team decided to look for the genes that actually encode the cancer's tumor antigens that the lymphocytes recognize. They identified the peptides within those antigens that were recognized by the immune system. One particular peptide from the gp100 molecule stood out. The study reported in this paper attempted to translate this molecular information into clinical results by immunizing patients against the gp100 peptide, which researchers had modified to boost its immunizing power: They'd produced a synthetic peptide by changing a single amino acid to increase the peptide's binding to HLA (human leukocyte-associated antigen) A2 molecules. "We were surprised by how effectively the peptide could result in the generation of immune T cells within the patients," remarks Rosenberg. "In fact, it was far more potent in the humans than it was in the experimental animals." But despite the ability to generate ample T cells, researchers only saw tumor regressions when they combined the peptide immunization with IL-2, though they got the most robust immune responses in the "peptide alone" arm of the study. "It's still an interesting paper because it was the first one to use those modified peptides with a larger panel of patients," says Frank O. Nestle, University of Zurich researcher and lead author of the melanoma vaccination study discussed above. In the last couple of years, Rosenberg and his colleagues have cloned several new genes that encode cancer antigens. They're now immunizing with multiple antigens instead of just one--including peptides that can raise not only CD8+ cells, as in this paper, but CD4+ cells. And his group is testing several other strategies for immunization--for example, inserting genes into recombinant viruses, or immunizing with naked DNA that encodes the antigens. "We're exploring a variety of different techniques to determine the best way to immunize a human against a cancer antigen now that we've finally identified the molecular nature of those cancer antigens," comments Rosenberg. Eugene Russo can be contacted at erusso@the-scientist.com. 1. S.A. Rosenberg et al., "Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma--a preliminary report," New England Journal of Medicine, 319:1676-80, 1988.

Synthetic Peptide Melanoma Vaccine

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