Cancer immunotherapy for solid tumors is coming of age, with FDA-approved immunotherapeutics in prostate cancer, melanoma, and renal cell cancer. Interleukin-2 (IL-2) and the CTLA4 antibody ipilimumab are approved for melanoma; both induce durable clinical regressions. Recent data also implicate antitumor immunity in clinical response to the BRAF inhibitor vemurafenib. Other very promising immune therapies are in development, with durable clinical regressions induced by blockade of PD-1/PD-L1 and by antigen-specific adoptive T cell therapy. There is excitement about this growing armamentarium of systemic immunotherapeutics, whose effects are mediated predominantly by T lymphocytes and whose effects are typically durable. Despite the effectiveness of those therapies, still about 70-80% of patients fail them, and go on to develop progressive disease. This is an ideal time to build on the armamentarium of immune and targeted therapies to build new combination therapies for advanced melanoma, with a goal of high rates of durable clinical benefit. Cancer vaccines inducing antigen-specific T cell responses are emerging as a component of combination immunotherapy. In the past 3 years, a cancer vaccine has been approved for prostate cancer, and a randomized prospective trial showed clinical value of adding a peptide vaccine to high-dose IL-2. Thus, after several decades of development and optimization, there is now evidence that cancer vaccines may improve clinical outcomes, in particular in combination with other active therapies. We have developed a vaccine with 6 intermediate-length peptides that induce CD4+ helper T (TH) cells (6 helper peptides, 6MHP), which is immunogenic in 40-80% of patients, has clinical activity in advanced melanoma with RECIST-defined response rates and disease control rates of 8% and 30%, respectively. Importantly, there also is a significant association between immune response to the 6MHP and survival. The current proposal is for a series of three clinical trials, to optimize the 6MHP vaccine with the AS 15 adjuvant (Aim 1), and to obtain preliminary data on whether combination with BRAF inhibition (Aim 2) or CTLA4 blockade (Aim 3) may improve clinical outcomes compared to either agent alone. The three clinical trials proposed in the application also will incorporate correlative studies of immune responses in blood, skin, lymph nodes, and tumor to obtain a more complete understanding of the host:tumor relationship in the context of these combination therapies.