Clonal expansion of Melan A-specific cytotoxic T lymphocytes in a melanoma patient responding to continued immunization with melanoma-associated peptides

Abstract

Peptides derived from human tumor antigens have been used in a number of clinical trials to induce specific immune responses against autologous tumors in cancer patients. Although favorable clinical results were observed in single patients, immune responses correlating with tumor regression were either not detected or in case of responses, the T-cell specificity was difficult to demonstrate. In this study, we analyzed antigen-specific T-cell responses induced in the skin and in peripheral blood lymphocytes (PBL) in an HLA-A2-positive melanoma patient. The patient showed major regression of metastatic melanoma under continued immunization with peptides derived from the melanocyte differentiation antigens Melan A/MART-1, tyrosinase and gp100/Pmel17. Based on the identification of different T-cell receptor (TCR) families reactive with Melan A/MART-1, we have demonstrated that i.d. immunization with peptides alone leads to oligoclonal expansion of Melan A/MART-1-specific cytotoxic T lymphocytes (CTL), detectable in local delayed-type hypersensitivity (DTH) reactions and PBL. A monoclonal expansion of a Melan A/MART-1-specific TCR VB 16 CTL was reproducibly observed after in vitro stimulation with Melan A/MART-1 peptides. The same TCR VB 16 CTL clone was detected in skin biopsies taken from vitiligo areas. Our findings provide strong evidence for the effective induction of specific T-cell responses to Melan A/MART-1 by i.d. immunization with peptide alone, which accounts for dermal depigmentation, specific cytotoxicity against Melan A/MART-1-expressing melanoma cells and clinical tumor regression.