Abstract 855: Dynamics of T cell and T cell receptor following mRNA-4157 (V940) plus pembrolizumab or pembrolizumab alone in resected melanoma from the mRNA-4157-P201 (KEYNOTE-942) trial

Abstract Introduction: mRNA-4157 is a novel mRNA-based individualized neoantigen therapy (INT) designed to enhance endogenous antitumor T-cell responses by targeting unique patient-specific tumor mutations. In the phase 2 mRNA-4157-P201 (KEYNOTE-942) trial, patients with completely resected high-risk stage IIIB-IV melanoma receiving mRNA-4157 + pembrolizumab (pembro) showed prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus those receiving pembro alone (Weber JS, et al. Lancet 2024). Here, we characterized the dynamics of T cell and T cell receptor (TCR) repertoire in peripheral blood following mRNA-4157 plus pembro or pembro alone. Methods: Patients were randomized 2:1 to receive mRNA-4157 + pembro or pembro alone. Whole blood samples from longitudinal time points (baseline: pre-pembro & pre-INT; post-pembro & pre-INT; post-pembro & post-INT; and longer-term follow-up after completion of treatment; 116, 101, 108, and 79 patients respectively) were collected and TCR sequencing was performed. TCR beta chains were down sampled and normalized to the top 10k clones by rank sum unique molecular identifier. Shannon clonality was calculated on down sampled data. Differential clone abundance between screening and on-treatment samples was calculated by binomial test. Results: Baseline TCR clonality was not associated with RFS of mRNA-4157 + pembro or pembro alone. However, longitudinal analysis of samples post-INT showed clonality was increased in 70% (55 out of 78) and 31% (12 out of 38) of the patients treated with mRNA-4157 + pembro and pembro alone, respectively. Analysis of clonotypes showed median number of novel expanded clonotypes after mRNA-4157 + pembro (n=78) and after pembro alone (n=38) was 38 and 22, respectively, suggesting that mRNA-4157 + pembro was associated with expansion of more novel clonotypes relative to pembro alone. Furthermore, among 78 patients in the mRNA-4157 + pembro arm, patients without recurrence (n=59) had median number of 40 novel expanded clonotypes while patients with recurrence (n=19) had median number of 16 novel expanded clonotypes. Additional analysis of neoantigen-specific T cells is ongoing and will be reported. Conclusions: Expansion of novel T cell clonotypes in peripheral blood was observed to a greater extent after mRNA-4157 + pembro compared to pembro alone, and the degree of novel expansion was associated with RFS. Citation Format: Min Lu, Ryan J. Sullivan, Jacky Chow, Janice M. Mehnert, Matteo S. Carlino, Adnan Khattak, George Ansstas, Matthew H. Taylor, Meredith McKean, Georgina V. Long, Mark B. Faries, Jason J. Luke, Anjali Rao, Laureen S. Ojalvo, Filippos Porichis, Igor Feldman, Lakshmi Srinivasan. Dynamics of T cell and T cell receptor following mRNA-4157 (V940) plus pembrolizumab or pembrolizumab alone in resected melanoma from the mRNA-4157-P201 (KEYNOTE-942) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 855.