CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib.
Hardikkumar JetaniIrene Garcia-CadenasThomas NerreterSimone ThomasJulian RydzekJavier Briones MeijideHalvard BonigWolfgang HerrJordi SierraHermann EinseleMichael HudecekPublished in: Leukemia (2018)
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.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- small molecule
- epidermal growth factor receptor
- low dose
- stem cells
- bone marrow
- signaling pathway
- big data
- deep learning
- cell therapy
- cell proliferation
- cancer therapy
- wild type
- single cell
- endoplasmic reticulum stress
- combination therapy
- artificial intelligence