Abstract 7128: Neoantigen expression and expansion of cytotoxic T cell clonotypes in multiple myeloma patients receiving a personalized cancer vaccine post-transplant: Insights from the BM CTN 1401 multicenter trial

Abstract Background: BMT CTN 1401 is a phase II trial of 140 multiple myeloma (MM) patients undergoing autologous hematopoietic cell transplant (HCT) followed by lenalidomide maintenance with or without a personalized DC/MM vaccine. Vaccination was associated with increased MM-reactive T cells and clonotypic expansion of activated T cells 1-year post-HCT. Here, we identify private or shared antigenic targets in pre-HCT bone marrow (BM) samples, along with corresponding T cell clonotypic patterns. We also further analyzed the peripheral blood (PB) immune landscape of the study patients, exploring the correlation between disease response and the T cell repertoire, including dominant clonotypes. Method: Pre-HCT BM samples from 16 patients underwent bulk RNAseq and whole exome sequencing. With an in silico-experimental framework developed by our team, we predicted tumor antigens by considering factors including translation potential, RNA expression, peptide-MHC binding affinity, immunogenicity, clonality, and physicochemical properties. 10 samples were further analyzed by single cell (sc) immunoprofiling to assess the antigens expression in MM cells. Additionally, PB samples from 40 study patients underwent sc immunoprofiling to investigate the T cell repertoire in stringent complete response/complete response (sCR/CR, N=26), very good partial response (VGPR, N=9), partial response (PR; N=4) or progressive disease (PD; N=1). Results: We observed a high prevalence of tumor-specific (neo)antigens, with 50% shared among more than 2 patients. 19 neoantigens were prioritized based on high immunogenicity and expression in multiple patients, including four expressed in immune-privileged tissues (MAGEC1, TPTE, UCHL1). UCHL1 showed an 80-fold higher median expression in MM samples than in healthy controls. We observed a significant enrichment of shared tumor antigenic peptides (n=33) across up to 10 patients, originating from regions not typically expressed or translated, such as retroelements and downstream/upstream open reading frames. PB T cells immunoprofiling revealed higher T cell clonotypic expansion in sCR/CR and VPGR, with sCR/CR associated with higher proportion of cytotoxic CD8 T cells and fewer Tregs 1-year post-HCT. A high degree of TCR sharing between clonally expanded T cells in the PB and BM was observed. Conclusions: To identify novel immunotherapy targets for MM, we characterized the MM antigenic landscape, identifying personal and shared tumor antigens. In addition, we demonstrated that sCR/CR is associated with clonal expansion of cytotoxic T cells with clonal dynamics in the PB reflecting those in the BM. We are correlating the dominant T cell clonotypes with the identified antigens and assessing the impact of DC/MM fusion vaccination in this setting. Citation Format: Giulia Cheloni, Dimitra Karagkouni, Shivani Nanda, Lina Bisharat, Isabella Saldarriaga, MA Yuling, Shuoshuo Wang, Xanti-Lida Katopodi, Yered Pita-Juarez, Jessica Liegel, Hazal Toros, Prateek Pophali, David Chung, Nina Shah, Natalie Callander, Binod Dhakal, Thinle Chodon, Nikhil Munshi, Kenneth Anderson, Yvonne Efebera, Peiman Hematti, Hillard Lazarus, Ehsan Malek, Philip McCarthy, Ajay Nooka, Krina Patel, Aaron Rapoport, Robert Soiffer, Edmund Waller, Marcelo Pasquini, Jacalyn Rosenblatt, Ioannis Vlachos, David Avigan. Neoantigen expression and expansion of cytotoxic T cell clonotypes in multiple myeloma patients receiving a personalized cancer vaccine post-transplant: Insights from the BM CTN 1401 multicenter 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 7128.