CAR T-cells targeting FLT3 have potent activity against FLT3 - ITD + AML and act synergistically with the FLT3-inhibitor crenolanib

Hardikkumar Jetani, Irene Garcia-Cadenas, Thomas Nerreter, Simone Thomas, Julian Rydzek, Javier Briones Meijide, Halvard Bonig, Wolfgang Herr, Jordi Sierra, Hermann Einsele, Michael Hudecek

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43 Citations (Scopus)

Abstract

© 2018 Macmillan Publishers Limited, part of Springer Nature. 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.
Original languageEnglish
Pages (from-to)1168-1179
JournalLeukemia
Volume32
Issue number5
DOIs
Publication statusPublished - 1 May 2018

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    Jetani, H., Garcia-Cadenas, I., Nerreter, T., Thomas, S., Rydzek, J., Meijide, J. B., Bonig, H., Herr, W., Sierra, J., Einsele, H., & 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