CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+AML and act synergistically with the FLT3-inhibitor crenolanib
Jetani H, Garcia-Cadenas I, Nerreter T, Thomas S, Rydzek J, Briones Meijide J, Bonig H, Herr W, Sierra J, Einsele H, Hudecek M (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 32
Pages Range: 1168-1179
Journal Issue: 5
DOI: 10.1038/s41375-018-0009-0
Abstract
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.
Involved external institutions
Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona
Spain (ES)
Universitätsklinikum Würzburg
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Goethe-Universität Frankfurt am Main
Germany (DE)
Spain (ES)
Universitätsklinikum Würzburg
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Goethe-Universität Frankfurt am Main
Germany (DE)
How to cite
APA:
Jetani, H., Garcia-Cadenas, I., Nerreter, T., Thomas, S., Rydzek, J., Briones Meijide, J.,... Hudecek, M. (2018). CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia, 32(5), 1168-1179. https://doi.org/10.1038/s41375-018-0009-0
MLA:
Jetani, Hardikkumar, et al. "CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+AML and act synergistically with the FLT3-inhibitor crenolanib." Leukemia 32.5 (2018): 1168-1179.
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