<h4>Purpose</h4>This randomized phase I/II clinical trial (NCT03617328) was designed to test whether administration of systemic agonistic anti-CD27 antibody (varlilumab) concurrent with a melanoma vaccine is safe and enhances vaccine immunogenicity.<h4>Patients and methods</h4>Adults with definitively treated, high-risk melanoma were randomized to receive a shared antigen vaccine targeting CD4+ T cells (6 melanoma helper peptides; 6MHP) either with (arm A) or without (arm B) systemic varlilumab over 11 weeks. The gene discussed is CD4; the disease is melanoma.