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

Journal of Hematology & Oncology

Zuyu Liang¹  Jieping Wei¹  Jian Yu¹  Jimin Shi¹  Xiaoqing Li¹  Wei Shan¹  Xiujian Wang¹  Mi Shao¹  Xinyi Teng¹  Yingli Han¹  Lijuan Ding¹  Yongxian Hu¹  Yi Luo¹  He Huang²  Hao Zhang³  Yulin Xu⁴  Penglei Jiang⁵  Pengxu Qian⁵  Hui Wang⁵  Jiazhen Cui⁶ 

[1] Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, China;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, China;Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, China;Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, China;Department of Hematology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, China;Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China;Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, China;Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China;Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China;

关键词: Chimeric antigen receptor T cells;    Acute lymphoblastic leukemia;    Tyrosine kinase inhibitor;    Dasatinib;    Differentiation;    Exhaustion;   

DOI  :  10.1186/s13045-021-01117-y

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY