Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma

SA Rosenberg, RM Sherry, KE Morton… - The Journal of …, 2005 - journals.aai.org
SA Rosenberg, RM Sherry, KE Morton, WJ Scharfman, JC Yang, SL Topalian, RE Royal…
The Journal of Immunology, 2005journals.aai.org
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 209–217 (210M). Vaccination using this altered peptide immunogen was …
Abstract
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 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+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ 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.
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