Randomized Phase I/II Clinical Trial of a Melanoma Helper Peptide Vaccine with or without Systemic Agonistic...

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.

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. A final vaccine was given at week 25 to assess memory response.

Thirty-three participants were treated at two centers. After enrolling 17 participants, the dose-limiting toxicity (DLT) rate with vaccine alone required protocol revision to limit local toxicity. Overall, DLT rates for arms A and B were 6% (1/17) and 31% (5/16), respectively. Twenty (61%) participants had CD4+ T-cell responses ex vivo. Persistent responses were detected in two (2/14, 14%) on arm A and one (1/16, 6%) on arm B. Memory response was detected in two (2/13, 15%) on arm A and four (4/16, 25%) on arm B. On arm A, there was a significant reduction in circulating CD4+ T cells. Four-year disease-free survival rates for arms A and B were 20% [95% confidence interval (CI), 6%-67%] and 69% (95% CI, 49%-96%), respectively.

No synergistic toxicity was observed with combination treatment. Similar durability in immunogenicity was found with or without varlilumab. Depletion of circulating CD4+ T cells with varlilumab may have abrogated benefits of inducing tumor-cognate CD4+ T cells with vaccination. Induction of memory responses supports further work to optimize shared antigen vaccines in combination with other immunotherapies.

Combination treatment with 6MHP vaccination and varlilumab was safe but did not improve CD4+ T-cell response rates. Circulating CD4+ T cells were reduced with varlilumab, and clinical outcome was improved without varlilumab. This study demonstrates induction of memory responses after shared antigen vaccination; however, CD27 agonism did not enhance durability of response. Depletion of CD4+ T cells after varlilumab may have interfered with the beneficial effects of vaccination.