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

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.

• Authors: Hao Zhang, Yongxian Hu, Mi Shao, Xinyi Teng, Penglei Jiang, Xiujian Wang, Hui Wang, 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
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 14 Issue 1 Pg. 113 (07 21 2021) ISSN: 1756-8722 [Electronic] England
• PMID: 34289897 (Publication Type: Letter, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• CD28 Antigens
• Protein Kinase Inhibitors
• Receptors, Chimeric Antigen
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Dasatinib

Topics

• Antineoplastic Agents (pharmacology)
• CD28 Antigens (immunology)
• Cell Culture Techniques (methods)
• Cell Differentiation (drug effects)
• Dasatinib (pharmacology)
• Humans
• Immunotherapy, Adoptive (methods)
• Lymphocyte Activation (drug effects)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (immunology, therapy)
• Protein Kinase Inhibitors (pharmacology)
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (cytology, drug effects, immunology)
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (immunology)