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

Mutated BRAF (BRAFV600E) is a potential immunotherapeutic target for melanoma because of its tumor specificity and expression in the majority of these lesions derived from different patients. BRAFV600E 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 BRAFV600E would suggest the feasibility of active specific immunotherapy targeting the mutation in these patients. In the present study, BRAFV600E 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 BRAFV600E-positive lesions showed lymphoproliferative responses to BRAFV600E 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 BRAFV600E-positive melanoma cells. None of the four patients with BRAFV600E-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 BRAFV600E peptides attractive candidate vaccines for these patients. (Cancer Res 2006; 66(6): 3287-93)