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Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 17% to 18.8% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR+) CD4+ and CD8+ T cells with concomitant decreases in naive CD4+ and CD8+ T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS+ CD4+ T cells, but not in ICOS+ CD8+ T cells or in FoxP3+ CD4+ regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.