NDLI: Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

Content Provider	Springer Nature : BioMed Central
Author	Zhang, Hao Hu, Yongxian Shao, Mi Teng, Xinyi Jiang, Penglei Wang, Xiujian Wang, Hui Cui, Jiazhen Yu, Jian Liang, Zuyu Ding, Lijuan Han, Yingli Wei, Jieping Xu, Yulin Li, Xiaoqing Shan, Wei Shi, Jimin Luo, Yi Qian, Pengxu Huang, He
Abstract	Relapses of CD19-expressing leukemia in patients who achieved initial remission after CART cell treatment have been reported to correlate with poor CART cells persistence. Sustained tonic signaling or strong activation drives CART cell differentiation and exhaustion, which limit the therapeutic efficacy and persistence of CART cells. Here, we identified dasatinib as the optimal candidate to prevent or reverse both CD28/CART and 4-1BB/CART cell differentiation and exhaustion during ex vivo expansion, which profoundly enhanced the therapeutic efficacy and in vivo persistence. Moreover, strong activation-induced CART cells differentiation, exhaustion and apoptosis driven by CD3/CD28 stimulation or antigen exposure were dramatically prevented or reversed by dasatinib treatment. Mechanistically, dasatinib markedly reduced the phosphorylation of Src and Lck, and downregulated the expression of genes involved in CAR signaling pathways, which resulted in the optimization of cell differentiation, exhaustion and apoptosis-related gene expression. Our study proposes a promising pharmacological approach for optimizing CART cells manufacture, and provides an experimental basis for reinvigorating CART cells in clinical application.
Related Links	https://jhoonline.biomedcentral.com/counter/pdf/10.1186/s13045-021-01117-y.pdf
Ending Page	6
Page Count	6
Starting Page	1
File Format	HTM / HTML
ISSN	17568722
DOI	10.1186/s13045-021-01117-y
Journal	Journal of Hematology & Oncology
Issue Number	1
Volume Number	14
Language	English
Publisher	BioMed Central
Publisher Date	2021-07-21
Access Restriction	Open
Subject Keyword	Oncology Hematology Cancer Research Chimeric antigen receptor T cells Acute lymphoblastic leukemia Tyrosine kinase inhibitor Dasatinib Differentiation Exhaustion
Content Type	Text
Subject	Hematology Cancer Research Oncology Molecular Biology
Journal Impact Factor	29.9/2023
5-Year Journal Impact Factor	27.1/2023

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