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

• Published in: Journal of hematology and oncology Vol. 14; no. 1; pp. 1 - 113
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 21.07.2021; BioMed Central; BMC
• Subjects: Acute lymphoblastic leukemia; Antigens; Apoptosis; CD19 antigen; CD28 antigen; CD3 antigen; Cell activation; Cell differentiation; Cell growth; Chimeric antigen receptor T cells; Chimeric antigen receptors; Dasatinib; Differentiation; Epigenetics; Exhaustion; Gene expression; Health aspects; Kinases; Lck protein; Letter to the Editor; Leukemia; Lymphocytes; Lymphocytes T; Nilotinib; Phosphorylation; Principal components analysis; Remission; Remission (Medicine); T cell receptors; T cells; Tyrosine; Tyrosine kinase inhibitor
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-021-01117-y

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. Keywords: Chimeric antigen receptor T cells, Acute lymphoblastic leukemia, Tyrosine kinase inhibitor, Dasatinib, Differentiation, Exhaustion