Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 14, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13045-021-01117-y
Keywords
Chimeric antigen receptor T cells; Acute lymphoblastic leukemia; Tyrosine kinase inhibitor; Dasatinib; Differentiation; Exhaustion
Categories
Funding
- National Natural Science Foundation of China [81730008, 81520108002, 81770201, 81970137, 81870080, 91949115]
- National Key R&D Program of China, Stem Cell and Translation Research [2018YFA0109300]
- Key Project of Science and Technology Department of Zhejiang Province [2018C03016-2, 2019C03016]
- Zhejiang Province Science Foundation for Distinguished Young Scholars [LR19H080001]
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Dasatinib has shown promising results in preventing or reversing differentiation and exhaustion of CAR-T cells, significantly enhancing therapeutic efficacy and in vivo persistence.
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.
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