期刊
JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 11, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13045-018-0603-7
关键词
Acute myeloid leukemia; Chimeric antigen receptor; FLT3; FLT3-ITD; Immunotherapy
资金
- National Natural Science Foundation of China [81430004, 81770181, 81700163]
- National Key Research and Development Program for Precision Medicine [2017YFC0909800]
- CAMS Initiative Fund for Medical Sciences [2016-I2M-1-007]
Background: Chimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients' blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3(+) AML, especially patients harboring FLT3-ITD mutation. Methods: The FLT3L CAR-T using FLT3 ligand as recognizing domain was constructed. The specific cytotoxicity against FLT3(+) leukemia cell lines, primary AML cells, and normal hematopoietic progenitor stem cells (HPSCs) in vitro were evaluated. In addition, FLT3(+) AML mouse model was used to assess the effect of FLT3L CAR-T therapy in vivo. Results: FLT3L CAR-T cells could specifically kill FLT3(+) leukemia cell lines and AML patients' bone marrow mononuclear cells in vitro (with or without FLT3 mutation) and have more potent cytotoxicity to FLT3-ITD cells. In a human FLT3(+) AML xenograft mouse model, FLT3L CAR-T cells could significantly prolong the survival of mice. Furthermore, it was found that FLT3L CAR-T cells could activate the FLT3/ERK signaling pathway of FLT3(+) leukemia cells with wild-type FLT3; meanwhile, it had no inhibitory effects on the colony formation of CD34(+) stem cells derived from normal human umbilical cord blood. Conclusions: The ligand-based FLT3L CAR-T cells could be a promising strategy for FLT3(+) AML treatment, especially those carried FLT3 mutation.
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