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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

ABSTRACT: The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

PROVIDER: PRJNA655350 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12390683_1.fastq.gz	Fastqsanger.gz
	SRR12390683_2.fastq.gz	Fastqsanger.gz
	SRR12390684_1.fastq.gz	Fastqsanger.gz
	SRR12390684_2.fastq.gz	Fastqsanger.gz
	SRR12390685_1.fastq.gz	Fastqsanger.gz

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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

Project description:Study aim: Investigate the effect of S-2HG (2-hydroxyglutarate) metabolite on the mRNA levels of human CD8 T cells Methods: Naïve CD8 T cells were isolated from human healthy donors. The CD8 T cells were aCD3/CD28 beads (1:1 bead-to-cell ratio) and IL-2 (30 U/ml) for 4 days. The cells were treated with S-2HG (0.4 mM) or vehicle (H2O) from the day of isolation and for 12 days before collection. Library preparation and paired-end RNA sequencing using Illumina NextSeq 500, as well as downstream data analysis, were performed by Active Motif.

2020-08-05 | GSE155715 | GEO

The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome.

Project description:Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG-treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG-treated CD19-CAR-T cells in patients with B-cell malignancies.

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Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

Project description:Chimeric antigen receptor modified T (CAR-T) cell therapy has limited efficacy against solid tumor, one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model, and found that knocking out BATF improved the performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, knocking out BATF endows T cells with improved resistance to exhaustion and better tumor eradication efficacy. We find that BATF binds to and up-regulates a subset of exhaustion genes in human CAR-T cells. Furthermore, BATF regulates the expression of genes involved in the development of effector and memory cells, and knocking out BATF shifts the population towards more central memory subset. Therefore, we conclude that BATF is a key factor limiting CAR-T cell function, and its depletion improves CAR-T cells efficacy against solid tumor.

2022-10-12 | GSE215086 | GEO

Paclitaxel resistance in ovarian cancer increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control

Project description:The microtubule-stabilising drug paclitaxel has activity in relapsed ovarian cancer. However, resistance frequently develops. Oncolytic adenoviruses are a novel cancer therapy, and replicate selectively within and lyse malignant cells, leading to productive infection of neighbouring cells. We found increased efficacy of adenoviruses of multiple subtypes in paclitaxel-resistant ovarian cancer cells. There was increased expression of a key adenovirus receptor, CAR (coxsackie adenovirus receptor), due to increased transcription that resulted from histone modification. Moreover, CAR transcription increased in intraperitoneal xenografts with acquired paclitaxel resistance and in tumours from patients with paclitaxel-resistant ovarian cancer. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer and that inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms. Parental SKOV3 and paclitaxel-resistant SKOV3-TR cells were analysed in duplicate

2015-12-10 | E-GEOD-54772 | biostudies-arrayexpress

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

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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]

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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]

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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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CAR Density Influences Antitumoral Efficacy of BCMA CAR T Cells and Correlates with Clinical Outcome [RNA-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 | GSE197843 | GEO

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

2022-10-05 | GSE197848 | GEO