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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [NECA_RNA-seq]

ABSTRACT: Investigation of the transcriptional profile of stimulated murine α-HER2 CAR T cells in the presence/absence of NECA and/or SCH58261

ORGANISM(S): Mus musculus

PROVIDER: GSE156189 | GEO | 2021/03/29

REPOSITORIES: GEO

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [murine_CRISPR_A2AKO_RNA-seq]

Project description:Investigation of the transcriptional profile of stimulated murine CRISPR/Cas9 MOCK and A2ARKO α-HER2 CAR T cells in the presence/absence of NECA

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [human_CRISPR_A2AKO_RNA-seq]

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy

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

2021-03-29 | GSE156192 | GEO

CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy

Project description:CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy

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Investigation of the transcriptional profile of stimulated HUMAN CRISPR/Cas9 MOCK and A2ARKO α-lewisY CAR T cells in the presence/absence of NECA

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [murine_CRISPR_A2AKO_RNA-seq]

Project description:CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [murine_CRISPR_A2AKO_RNA-seq]

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [human_CRISPR_A2AKO_RNA-seq]

Project description:CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [human_CRISPR_A2AKO_RNA-seq]

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CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [NECA_RNA-seq]

Project description:CRISPR/Cas9 mediated deletion of the adenosine A2AR enhances CAR T cell efficacy [NECA_RNA-seq]

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CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy.

Project description:Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.

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Antagonism of IAPs enhances CAR T cell efficacy

Project description:Chimeric antigen receptor (CAR) T cell therapy has proven highly successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrate that antagonizing Inhibitor of Apoptosis Proteins (IAPs) with the clinical smac-mimetic, birinapant, significantly enhanced the anti-tumor activity of CAR T cells in a TNF-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T cell-derived TNF. Importantly, combining CAR T cell therapy with birinapant dramatically reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrate the synergistic potential of combining CAR T cell therapy with smac-mimetics. Taken together, we identify CAR T cell-derived TNF as a potent anti-tumor effector, which can be further harnessed by smac-mimetics.

2019-02-01 | GSE124140 | GEO

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