Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8 super(+) T Cells in Patients with Melanoma

• Published in: The Journal of immunology (1950) Vol. 175; no. 9; pp. 6169 - 6176
• Main Authors: Rosenberg, Steven A, Sherry, Richard M, Morton, Kathleen E, Scharfman, William J, Yang, James C, Topalian, Suzanne L, Royal, Richard E, Kammula, Udai, Restifo, Nicholas P, Hughes, Marybeth S, Schwartzentruber, Douglas, Berman, David M, Schwarz, Susan L, Ngo, Lien T, Mavroukakis, Sharon A, White, Donald E, Steinberg, Seth M
• Format: Journal Article
• Language: English
• Published: 01.11.2005
• ISSN: 0022-1767

The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100 sub(209-217(210M)). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8 super(+) T cells assessed by tetramer analysis. From 1 to 10% of all CD8 super(+) cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.