A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CART cells and gilteritinib

作者：Li, Ke-xin; Wu, Hui-yang; Pan, Wan-ying; Guo, Meng-qi; Qiu, De-zhi; He, Yan-jie; Li, Yu-hua; Yang, Dong-Hua^*; Huang, Yu-xian^*

来源：Molecular Cancer, 2022, 21(1): 66.

DOI：10.1186/s12943-022-01541-9

• Acute myeloid leukaemia
• Chimeric antigen receptor (CAR)
• Immunotherapy
• Natural killer group 2 member D (NKG2D)
• FMS-like tyrosine kinase 3 (FLT3)
• FLT3 inhibitor
• Gilteritinib

Background: Patients with relapsed/refractory acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have limited treatment options and poor prognosis. Therefore, novel treatment modalities are needed. Since high expression of natural killer group 2 member D ligands (NKG2DLs) can be induced by FLT3 inhibitors, we constructed dual-target FLT3 single-chain fragment variable (scFv)/NKG2D-chimeric antigen receptor (CAR) T cells, and explored whether FLT3 inhibitors combined with FLT3scFv/NKG2D-CART cells could have synergistic anti-leukaemia effects. @@@ Methods: FLT3scFv and NKG2D expression in CART cells, FLT3 and NKG2DL expression in AML cells, and the in vitro cytotoxicity of combining CART cells with gilteritinib were assessed by flow cytometry. The therapeutic effect was evaluated in a xenograft mouse model established by injection of MOLM-13 cells. Mechanisms underlying the gilteritinib-induced NKG2DL upregulation were investigated using siRNA, ChIP-QPCR and luciferase assays. @@@ Results: The FLT3scFv/NKG2D-CART cells specifically lysed AML cells both in vitro and in the xenograft mouse model. The efficacy of FLT3scFv/NKG2D-CART cells was improved by gilteritinib-pretreatment. The noncanonical NF-kappa B2/Rel B signalling pathway was found to mediate gilteritinib-induced NKG2DL upregulation in AML cells. @@@ Conclusions: Bispecific FLT3scFv/NKG2D-CART cells can effectively eradicate AML cells. The FLT3 inhibitor gilteritinib can synergistically improve this effect by upregulating NF-kappa B2-dependent NKG2DL expression in AML cells.

• 单位
  南方医科大学