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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197851 | GEO | 2022/10/05

REPOSITORIES: GEO

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

| PRJNA812509 | ENA

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]

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Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma.

Project description:Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes.Methods: We performed a database search using the terms "BCMA," "CAR," and "multiple myeloma" for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332).Results: Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0-88.2); 10.5% (6.8-16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3-26.7; I2?=?45%) versus 2.8% (1.3-6.1; I2?=?0%) (p?<?0.0001). The pooled overall response rate was 80.5% (73.5-85.9); complete responses (CR) were observed in 44.8% (35.3-54.6). A pooled CR rate of 71.9% (62.8-79.6; I2?=?0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5-41.1; I2?=?67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4-17.4) months, which compared favorably to the expected PFS of 1.9 (1.5-3.7) months (HR 0.14; p?<?0.0001).Conclusions: Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

| S-EPMC7713173 | biostudies-literature

Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages

Project description:The advent of CAR T cells targeting CD19 or BCMA on B cell neoplasm demonstrated remarkable efficacy, but rapid relapses and primary refractoriness remains challenging. A leading cause of CAR T cell failure is their lack of expansion and limited persistence. Long-lived, self-renewing multipotent T memory stem cells (TSCM) and T central memory cells (TCM) likely sustain superior tumor regression, but their low frequencies in blood from cancer patients impose a major hurdle for clinical CAR T production. We designed a clinically compliant protocol for generating BCMA CAR T cells starting with increased TSCM/TCM cell input. A CliniMACS Prodigy process was combined with flow cytometry-based enrichment of CD62L+CD95+ T cells. Although starting with only 15% of standard T cell input, the selected TSCM/TCM material was efficiently activated and transduced with a BCMA CAR-encoding retrovirus. Cultivation in the presence of IL-7/IL-15 enabled the harvest of CAR T cells containing an increased CD4+ TSCM fraction and 70% TSCM cells amongst CD8+. Strong cell proliferation yielded cell numbers sufficient for clinical application, while effector functions were maintained. Together, adaptation of a standard CliniMACS Prodigy protocol to low input numbers resulted in efficient retroviral transduction with a high CAR T cell yield. Graphical Abstract CAR T cell therapies can fail when these cells disappear. Rehm and colleagues demonstrate a procedure for T memory stem cell-enrichment (TSCM) using FACS combined with bioreactor expansion. Despite low TSCM frequencies in patients, this technology is suitable for providing clinical scale BCMA CAR T cells, facilitating extended persistence and tumor control.

| S-EPMC8791860 | biostudies-literature

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