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CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome

ABSTRACT: CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome

PROVIDER: PRJNA812509 | ENA |

REPOSITORIES: ENA

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CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [scRNA-seq]

Project description:CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [scRNA-seq]

| PRJNA812508 | ENA

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [RNA-seq]

Project description:CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [RNA-seq]

| PRJNA812498 | ENA

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [ATAC-seq]

Project description:CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [ATAC-seq]

| PRJNA812511 | ENA

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [scRNA-seq]

Project description:In this work, we address the impact of CAR density on the in vitro and in vivo functionality of BCMA-CAR T cells. Phenotypic, functional, transcriptomic and epigenomic studies at bulk and single cell level revealed different profiles between CAR T cells with high and low expression of the CAR molecule (CARHigh and CARLow T cells). We analyzed the phenotype of CARHigh and CARLow T cell populations before and after stimulation with tumor cells. Sorted CD4+ and CD8+ CARHigh and CARLow T cell populations from six different CAR T cell productions were profiled using high-throughput RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin (ATAC-seq). To better understand the heterogeneity of CAR T cells and the influence of CAR level on their transcriptomic profile, we performed single cell transcriptomic analysis on 43,981 CAR T cells from three independent productions.

2022-10-05 | GSE197848 | GEO

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [RNA-seq]

2022-10-05 | GSE197843 | GEO

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [ATAC-seq]

2022-10-05 | GSE197849 | GEO

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome.

Project description:Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.

| S-EPMC9524842 | biostudies-literature

CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-05 | GSE197851 | GEO

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with Multiple Myeloma

Project description:Chimeric antigen receptor T-cells (CAR-T) targeting B-cell-maturating-antigen (TNRFSF17, BCMA) show unprecedented overall response rates of up to 100% in heavily pretreated relapsed-refractory Multiple Myeloma (RRMM). However, the efficiency of the treatment is hindered by the rapid emergence of tumor-intrinsic mechanisms of resistance. We herein describe a patient with RRMM and extramedullary disease (EMD) who underwent Idecabtagene vicleucel BCMA CAR-T therapy. The patient rapidly achieved very good partial response including full resolution of EMD, but aggressively relapsed 5 months after CAR T cell infusion. Single cell RNA sequencing and immunohistochemistry on the re-emerging tumor cells demonstrated loss of target expression on mRNA and protein levels, and whole genome sequencing revealed the homozygous deletion of Chr 16p1313, including the BCMA locus. Clonal heterogeneity of BCMA could be observed in 32 RRMM patients from our institution. In three of them heterozygous deletion of BCMA could be confirmed, with none of them having underwent prior anti-BCMA therapy. Thus, our report not only provides first evidence of BCMA loss as the underlying mechanism of disease relapse following BCMA targeted immunotherapy in MM. It furthermore identifies a subset of patients at risk to develop biallelic BCMA inactivation thus linking genomic instability in MM to relapse from targeted immunotherapies.

2020-12-30 | GSE143317 | GEO

Reconstitution of the Multiple Myeloma Microenvironment Following Lymphodepletion with BCMA CAR-T Therapy

Project description:Despite the acknowledged effectiveness of BCMA chimeric antigen receptor T (CAR-T) cells in killing multiple myeloma (MM) cells, predicting treatment responsivity to BCMA CAR-T therapy remains a challenge. In this study, we demonstrated that the best overall responses (BORs) of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells (Tregs), enhanced CD8+ effector T cell cytotoxic activity, and elevated type 1 conventional dendritic cell (cDC1) antigen presentation ability. Our study sheds light on MM microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

2024-07-10 | GSE271915 | GEO

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