Phase I trial of a heat-conditioned tumor lysate vaccine (TRIMELVax) in anti-PD-1 refractory melanoma: safety and immunological aspects (NCT06556004)

Background: TRIMELVax is a cancer vaccine prototype derived from heat-conditioned melanoma cell lysates combined with a natural adjuvant. Preclinical studies demonstrated robust antitumor immune responses and tumor regression. We conducted a Phase I clinical trial to evaluate the safety, tolerability, immunogenicity, and preliminary efficacy of TRIMELVax in patients with unresectable stage IV melanoma who had progressed after first-line anti-PD-1 therapy. Methods: Eligible patients had stage IV melanoma with documented progression or unacceptable toxicity following anti-PD-1 treatment. TRIMELVax was administered subcutaneously every four weeks for a total of four doses. The primary endpoints of the study were safety and feasibility, which were assessed according to CTCAE v5.0. Secondary endpoints included efficacy as assessed by RECIST 1.1, overall survival (OS), progression-free survival (PFS), and immunogenicity, evaluated by peripheral blood immune cell responses and delayed-type hypersensitivity (DTH) reactions. Results: Seventeen patients received ≥ 1 dose; 13 completed all four doses. Treatment-related adverse events occurred in 9 patients, with a grade 1 or 2 severity. Two patients experienced manageable grade 3 events. No grade 4–5 toxicities were observed. No complete responses were observed in this cohort. Notably, a partial response was observed in 1 patient, stable disease in 6 patients, yielding a 41% disease control rate; 10 patients progressed. Median OS was 14 months, and median PFS was 5.2 months. DTH positivity was observed in six of the nine patients tested, correlating with the induction of memory T cells in peripheral blood after treatment. Immunomonitoring revealed increased CXCR3 expression in CD8⁺ T cells and decreased CD39 expression in both CD4⁺ and CD8⁺ subsets in patients with disease control. One case with lung metastasis regression exhibited a significant expansion of TCF1⁺PD-1⁺ CD4⁺ and CD8⁺ T cell populations, and an enriched perforin⁺granzyme B⁺ CD8⁺ T cell compartment, consistent with vaccine-associated immune activation. Conclusions: TRIMELVax demonstrated acceptable safety and early signs of clinical activity in anti-PD-1 refractory melanoma patients. These findings support its immunogenic potential and warrant further evaluation in larger, controlled studies. CLINICALTRIAL.GOV: NCT06556004.