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IL-2-inducible T cell kinase deficiency enables development of sustainable chimeric antigen receptor T cell therapy [scRNA-seq]

ABSTRACT: Despite the revolutionary achievements of chimeric antigen receptor (CAR) T cell therapy in treating cancers, especially leukemia, several significant challenges still limit its therapeutic efficacy. Of particular relevance is the relapse of cancer in large part, as a result of exhaustion and short persistence of CAR-T cells in vivo. IL-2-inducible T cell kinase (ITK) is a critical modulator of the strength of TCR signaling, while its role in CAR signaling is unknown. By electroporation of Cas9 ribonucleoprotein (RNP) complex into CAR-T cells, we successfully deleted ITK in CD19-CAR-T cells with high efficiency. Bulk and single-cell RNA sequencing (scRNA-seq) analyses revealed down-regulation of exhaustion and up-regulation of memory gene signatures in ITK-deficient CD19-CAR-T cells. Our results further demonstrated a significant reduction of T cell exhaustion and enhancement of T cell memory, with significant improvement of CAR-T cell expansion and persistence both in vitro and in vivo. Moreover, ITK-deficient CD19-CAR-T cells showed better control of tumor relapse. Our work provides a promising strategy of targeting ITK to develop sustainable CAR-T products for clinical use.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278612 | GEO | 2024/11/20

REPOSITORIES: GEO

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IL-2-inducible T cell kinase deficiency enables development of sustainable chimeric antigen receptor T cell therapy [bulk RNA-seq]

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