CAR T-cells targeting FLT3 have potent activity against FLT3(-)ITD(+) AML and act synergistically with the FLT3-inhibitor crenolanib
Por:
Jetani, H, Garcia-Cadenas, I, Nerreter, T, Thomas, S, Rydzek, J, Meijide, JB, Bonig, H, Herr, W, Sierra, J, Einsele, H, Hudecek, M
Publicada:
1 may 2018
Resumen:
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.
Filiaciones:
Jetani, H:
Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany
Garcia-Cadenas, I:
Autonomous Univ Barcelona, St Pau & Jose Carreras Leukemia Res Inst, Hematol Dept, Hosp Santa Creu & St Pau, Barcelona, Spain
Nerreter, T:
Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany
Thomas, S:
Univ Klinikum Regensburg, Klin & Poliklin Innere Med 3, Regensburg, Germany
Rydzek, J:
Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany
Meijide, JB:
Autonomous Univ Barcelona, St Pau & Jose Carreras Leukemia Res Inst, Hematol Dept, Hosp Santa Creu & St Pau, Barcelona, Spain
Bonig, H:
Goethe Univ Frankfurt, Inst Transfus Med & Immunhamatol, Frankfurt, Germany
Deutsch Rotes Kreuz Blutspendedienst BaWuHe, Frankfurt, Germany
Herr, W:
Univ Klinikum Regensburg, Klin & Poliklin Innere Med 3, Regensburg, Germany
Sierra, J:
Autonomous Univ Barcelona, St Pau & Jose Carreras Leukemia Res Inst, Hematol Dept, Hosp Santa Creu & St Pau, Barcelona, Spain
Einsele, H:
Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany
Hudecek, M:
Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany
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