Jetani, Hardikkumar and Garcia-Cadenas, Irene and Nerreter, Thomas and Thomas, Simone and Rydzek, Julian and Briones Meijide, Javier and Bonig, Halvard and Herr, Wolfgang and Sierra, Jordi and Einsele, Hermann and Hudecek, Michael (2018) CAR T-cells targeting FLT3 have potent activity against FLT3(-)ITD(+) AML and act synergistically with the FLT3-inhibitor crenolanib. LEUKEMIA, 32 (5). pp. 1168-1179. ISSN 0887-6924, 1476-5551
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; CHIMERIC ANTIGEN RECEPTORS; TYROSINE KINASE; B-CELL; EXPRESSION; INHIBITOR; MUTATIONS; RESISTANCE; ANTIBODY; DOMAIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Mar 2020 13:49 |
| Last Modified: | 04 Mar 2020 13:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14613 |
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