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Background For patients with high-risk melanoma who are unresponsive or intolerant to immune checkpoint inhibitors, cancer vaccines may provide benefit with a favorable toxicity profile. CD4 + T cells provide essential help to dendritic cells (DCs) for optimal CD8+ T cell priming in the antitumor response, and induction of tumor-cognate CD4+ T cell responses may enhance vaccine efficacy. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine composed of six non-mutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen helper peptide (mBRAF) co-administered locally with a TLR3 agonist (poly-ICLC) and agonistic CD40 antibody (CDX-1140).Methods Adults with high-risk melanoma arising from cutaneous, mucosal, or ocular primary sites who were rendered clinically free of disease after definitive treatment were enrolled to this nonrandomized phase I/II trial ( NCT04364230) designed to assess safety and immunogenicity. Participants received vaccine (6MHP+mBRAF+poly-ICLC) with a dose-escalation allocation of CDX-1140 into the vaccine mixture at one of four dose levels (50, 200, 800, 3000 μg). Vaccines were administered at 3-week intervals for four doses. Primary endpoints were safety and peripheral CD4+ T cell response. Exploratory analysis to characterize the vaccine site microenvironment was performed.Results Of 22 eligible participants, 11 (50%) had ocular melanoma. Sixteen (73%) received the maximum CDX-1140 dose. Toxicities were limited to grade 1 or 2 treatment-related adverse events, with no dose-limiting toxicities reported. Peripheral CD4 + T cell responses to 6MHP were found ex vivo in six (27%, 95% CI 11% to 50%), including four with the maximum CDX-1140 dose. One had a durable and persistent T cell response to week 25. T cell responses to mBRAF did not meet criteria for positivity ex vivo, but one participant had a durable response after in vitro stimulation, with expansion of multifunctional Th1-polarized CD4+ T cells. Favorable immune-related changes were observed at the vaccine site, including CDX-1140-mediated increases in mature (DC-LAMP+) DCs.Conclusions The vaccine was safe, well-tolerated, and immunogenic. Optimization of vaccines that include agonistic CD40 antibody is needed to enhance immunogenicity. Induction of a multifunctional CD4 + T cell response to mBRAF supports targeting shared mutated neoantigens with melanoma vaccines.Trial registration number NCT04364230.