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Background mRNA-4359 is an investigational immunotherapy designed to activate antigen-specific T cells that target both PD-L1 and IDO1 expressed by tumor and immunosuppressive cells. By promoting T-cell responses and reshaping the tumor microenvironment (TME), mRNA-4359 may enhance the efficacy of immune checkpoint blockade in resistant settings. Here, we present peripheral and tumor translational data from checkpoint inhibitor resistant/refractory (CPI-R/R) melanoma patients (pts) treated with mRNA-4359 plus pembrolizumab.Methods In an ongoing trial ( NCT05533697), as of 28Feb2025, 29 patients with CPI-R/R melanoma received pembrolizumab (400 mg IV Q6W) plus mRNA-4359 (400 µg [n=14] or 1000 µg [n=15] IM, Q3W, up to 9 doses. Peripheral and tumor samples collected pre- and on-treatment were analyzed for antigen-specific T cell responses, T cell clonality, ctDNA, and features of an immune-inflamed TME.Results Twenty-five pts were response-evaluable with objective response rate (ORR) of 24% (n = 6, 1 complete responder, CR; 5 partial responders, PR) and disease control rate (DCR) of 60% (n=15: 6 ORRs + 9 stable disease, SD). Peripheral PD-L1- or IDO1-specific T cell responses were detected post-treatment after in vitro expansion in majority of pts with evaluable samples (11/16, 69%). Treatment led to increases of novel expanded T cell receptor (TCR) clones over time across both dose groups (n=23). The median peak number of novel expanded TCR clones was higher in responders, with clone counts of 82 in CR (n=1), 67 in PR (n=5), 24 in SD (n=8), and 22 in progressive disease (PD, n=9), assessed up to 269 days post-treatment. A few peripherally expanded TCR clones were also detected in responder tumors 3 weeks after the first dose, and most responders (4/5) show >95% reduction in ctDNA tumor methylation score at week 6.Among 23 pts with baseline biopsy, dual gene expression of PD-L1 and IDO1 was higher in responders, which correlated with an immune inflamed phenotype. On-treatment tumor samples showed increases in immune-inflamed gene signatures related to T cell inflammation and antigen presentation, which were ≥2-fold higher in PR (n=4) compared to pts with SD or PD (n=11). Responders (n=4) exhibited greater increases in T cell infiltration compared to non-responders (n=11), with 6.2-fold and 1.9-fold higher levels for CD4 and CD8 T cells, respectively.Conclusions mRNA-4359 plus pembrolizumab may restore immune responsiveness in CPI-R/R melanoma by priming antigen-specific T cells, expanding de novo TCR clones, and creating a more inflamed TME with increased T cell infiltration, allowing for restoration of checkpoint inhibitor response.Acknowledgements This study was funded by Moderna, Inc.Ethics Approval The protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.