Single-Cell Profiling Reveals Contribution of Tumor Extrinsic and Intrinsic Factors to BCMA-Targeted CAR-T Cell Efficacy in Multiple Myeloma

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.326-326
• Main Authors: Melnekoff, David T., Ghodke-Puranik, Yogita, Van Oekelen, Oliver, Aleman, Adolfo, Upadhyaya, Bhaskar, Sebra, Robert, Jagannath, Sundar, Lagana, Alessandro, Parekh, Samir
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-150923

▪ Background: BCMA CAR-T cell therapy has shown great promise in relapsed/refractory multiple myeloma (RRMM) patients, even though there is unpredictable variability in the duration and depth of response. The mechanisms behind these divergent outcomes and relapse are not well understood and heterogeneity of MM patients at the level of both tumor genomics and tumor microenvironment (TME) likely contributes to this important knowledge gap. To explore this question, we performed a longitudinal high resolution single cell genomic and proteomic analysis of bone marrow (BM) and peripheral blood (PB) samples in MM patients treated with BCMA CAR-T. Methods: Longitudinal comprehensive immune phenotyping of 3.5 million peripheral blood mononuclear cells (PBMC, CD45+CD66b-) from 11 BCMA CAR-T (idecabtagene vicleucel, ide-cel) patients was achieved via mass cytometry (CyTOF) with a panel of 39 markers. In addition, a total of 45,161 bone marrow mononuclear cells (BMMC) were analyzed from 6 patients before initiation of ide-cel therapy and at relapse by unbiased mRNA profiling via single-cell RNA-seq (scRNA-seq) using the GemCode system (10x Genomics). Downstream analysis was performed using the CATALYST and Seurat R packages, respectively. Immune cell populations are reported as % of PBMC and CD138- BMMC respectively, unless noted otherwise. Reported p values correspond to non-parametric tests or paired t test where applicable. Results: We compared baseline immune cell populations in the PB and the TME (BM) with regards to depth of CAR-T response. In PB, good responders (≥VGPR) had a higher proportion of CD8+ T cells (37% in good vs 11% in poor responders (