Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion
Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion
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DOI：
10.1186/s13045-021-01117-y
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发表时间：
2021
影响因子：
28.5
通讯作者：
He Huang
中科院分区：
文献类型：
--
作者：
Hao Zhang;Yongxian Hu;Mi Shao;Xinyi Teng;Penglei Jiang;Xiujian Wang;Wang Hui;Jiazhen Cui;Jian Yu;Zuyu Liang;Lijuan Ding;Yingli Han;Jieping Wei;Yulin Xu;Xiaoqing Li;Wei Shan;Jimin Shi;Yi Luo;Pengxu Qian;He Huang
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.
