癌症研究
造血
Fms样酪氨酸激酶3
川地34
嵌合抗原受体
髓系白血病
祖细胞
干细胞
白血病
T细胞
生物
免疫学
细胞生物学
免疫系统
生物化学
基因
突变
作者
Hardikkumar Jetani,Irene García‐Cadenas,Thomas Nerreter,Simone Thomas,Julian Rydzek,Javier Briones Meijide,Halvard Bönig,Wolfgang Herr,Jordi Sierra,Hermann Einsele,Michael Hudecek
出处
期刊:Leukemia
[Springer Nature]
日期:2018-02-05
卷期号:32 (5): 1168-1179
被引量:138
标识
DOI:10.1038/s41375-018-0009-0
摘要
FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed on normal hematopoietic stem and progenitor cells (HSC) and retained on malignant blasts in acute myeloid leukemia (AML). We engineered CD8+ and CD4+ T-cells expressing a FLT3-specific chimeric antigen receptor (CAR) and demonstrate they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3 or FLT3 with internal tandem duplication (FLT3-ITD). We also show that treatment with the FLT3-inhibitor crenolanib leads to increased surface expression of FLT3 specifically on FLT3-ITD+ AML cells and consecutively, enhanced recognition by FLT3-CAR T-cells in vitro and in vivo. As anticipated, we found that FLT3-CAR T-cells recognize normal HSCs in vitro and in vivo, and disrupt normal hematopoiesis in colony-formation assays, suggesting that adoptive therapy with FLT3-CAR T-cells will require subsequent CAR T-cell depletion and allogeneic HSC transplantation to reconstitute the hematopoietic system. Collectively, our data establish FLT3 as a novel CAR target in AML with particular relevance in high-risk FLT3-ITD+ AML. Further, our data provide the first proof-of-concept that CAR T-cell immunotherapy and small molecule inhibition can be used synergistically, as exemplified by our data showing superior antileukemia efficacy of FLT3-CAR T-cells in combination with crenolanib.
科研通智能强力驱动
Strongly Powered by AbleSci AI