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Human Leukocyte Antigen-A2–Restricted CTL Responses to Mutated BRAF Peptides in Melanoma Patients

¹ The Wistar Institute; ² Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center; ³ Department of Pathology, ⁴ Hematology-Oncology Division, Department of Medicine, and ⁵ Division of Surgical Oncology, Department of Surgery, Hospital of the University of Pennsylvania; ⁶ Melanoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; and ⁷ Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland

Requests for reprints: Dorothee Herlyn, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-898-3962; Fax: 215-898-0980; E-mail: dherlyn{at}wistar.org.

Mutated BRAF (BRAF^V600E) is a potential immunotherapeutic target for melanoma because of its tumor specificity and expression in the majority of these lesions derived from different patients. BRAF^V600E is expressed intracellularly and not on the cell surface, therefore providing a target for T cells but not B cells. Demonstration of patients' T cell responses to BRAF^V600E would suggest the feasibility of active specific immunotherapy targeting the mutation in these patients. In the present study, BRAF^V600E peptides with putative binding sites for human leukocyte antigen (HLA)-A2 were used to stimulate T lymphocytes of HLA-A2–positive melanoma patients. Four of five patients with BRAF^V600E-positive lesions showed lymphoproliferative responses to BRAF^V600E peptide stimulation. These responses were specific for the mutated epitope and HLA-A2 was restricted in three patients. Lymphocytes from these three patients were cytotoxic against HLA-A2–matched BRAF^V600E-positive melanoma cells. None of the four patients with BRAF^V600E-negative lesions and none of five healthy donors had lymphoproliferative responses specific for the mutated epitope. The high prevalence (50%) of HLA-A2 among melanoma patients renders HLA-A2–restricted BRAF^V600E peptides attractive candidate vaccines for these patients. (Cancer Res 2006; 66(6): 3287-93)