CD4 T cell response to cancer antigen may improve cancer vaccine monitoring

By identifying an immunodominant epitope of the tumor antigen SSX-2 gene product that binds to CD4 T cells, researchers believe they are closer to developing a therapeutic vaccine effective for treating multiple cancer types. CD4 T cell responses are also expected to enhance monitoring of cancer vaccine responses in clinical trials.

Genes of the SSX family, a cancer/testis antigen, are produced by gametogenic cells and cancer cells, but not by normal tissue, Dr. Danila Valmori and associates explain in the Journal of Clinical Investigation for April 15th. However, natural immune responses to SSX-2 are limited and occur late in the disease evolution. Therefore, vaccines targeted to SSX-2-derived sequences are being developed to initiate strong, early immune responses to tumors.Dr. Valmori, at Columbia University College of Physicians and Surgeons in New York, and investigators previously identified SSX-2-derived epitopes recognized by tumor-reactive CD8 T cells. But because CD4 T cells are important for initiating, amplifying, and maintaining CD8 T cell and B cell responses, CD4 T cell epitopes are considered a crucial component of effective cancer vaccines.Using T cells isolated from a melanoma patient who had a spontaneous CD8 cell response to another epitope of SSX-2, the authors identified a CD4 cell-specific epitope mapping to the 37-58 region of the protein.They synthesized this peptide and incubated it with CD4 T cells isolated from 19 melanoma patients and eight healthy donors. Because cells from 11 patients but none of the cells from healthy subjects responded to SSX-2 37-58, the researchers suggest that this is an immunodominant epitope for CD4 cells. SSX gene products are “expressed in many different tumor types, such as sarcoma, lung cancer, and breast cancer,” Dr. Valmori told Reuters Health, so vaccines using recombinant SSX proteins should be effective against any of these cancers.Her group is scheduled to begin a phase I trial before the end of the year, using the CD8 T cell-specific SSX-2-derived epitope they had previously developed. Because the SSX-2 37-58 peptide described in their current paper is so new, it will not be incorporated into the new vaccine, but will be useful in monitoring the immune responses.Using tumor response as an end point, it would take extended periods of time to see if the vaccine works, she explained. “But now, with immune monitoring, we can follow patients on a weekly basis to see exactly how they are responding.”Within 3 or 4 years, she added, “we hope to have a vaccine incorporating five or six SSX antigens together,” including the epitope recognized by CD4 cells, that could provide more comprehensive protection in a large proportion of patients with cancer.(Source: J Clin Invest 2004: Reuters Health: Karla Gale: Oncolink: April 2004)