Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells.
Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells.
复制标题
使用基于配体的嵌合抗原受体工程 T 细胞靶向急性髓系白血病中的 FLT3
DOI：
10.1186/s13045-018-0603-7
复制
发表时间：
2018-05-02
影响因子：
28.5
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang Y;Xu Y;Li S;Liu J;Xing Y;Xing H;Tian Z;Tang K;Rao Q;Wang M;Wang J
背景嵌合抗原受体工程T细胞(CAR-T)在治疗淋巴母细胞白血病方面具有非凡的疗效。然而，使用CAR-T细胞治疗急性髓系白血病(AML)仍然是有限的。白血病的发生总是与细胞遗传学的异常有关，近三分之一的AML患者存在FMS样酪氨酸激酶3(Flt3)的激活突变，这提示预后不良。考虑到Flt3在AML患者原始细胞中的表达，CAR-T可能成为治疗Flt3+AML，尤其是携带Flt3-ITD突变的患者的新的候选靶点。检测其对Flt3+白血病细胞系、原代AML细胞和正常造血祖干细胞(HPSCs)的体外杀伤活性。结果FLT3L CAR-T细胞能在体外(含或不含Flt3突变)特异性杀伤Flt3+白血病细胞株和AML患者骨髓单个核细胞，对Flt3-ITD细胞具有较强的细胞毒作用。在人Flt3+AML异种移植小鼠模型中，Flt3L CAR-T细胞能显著延长小鼠的存活时间。同时发现，Flt3L CAR-T细胞可激活Flt3+白血病细胞的Flt3/ERK信号通路，同时对正常人脐血CD34+干细胞集落形成无抑制作用。结论基于配体的Flt3LCAR-T细胞可作为治疗Flt3+AML，尤其是携带Flt3基因突变的AML的一种有前景的策略。
BackgroundChimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients’ blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3+AML, especially patients harboring FLT3-ITD mutation.MethodsThe FLT3L CAR-T using FLT3 ligand as recognizing domain was constructed. The specific cytotoxicity against FLT3+leukemia cell lines, primary AML cells, and normal hematopoietic progenitor stem cells (HPSCs) in vitro were evaluated. In addition, FLT3+AML mouse model was used to assess the effect of FLT3L CAR-T therapy in vivo.ResultsFLT3L CAR-T cells could specifically kill FLT3+leukemia cell lines and AML patients’ bone marrow mononuclear cells in vitro (with or without FLT3 mutation) and have more potent cytotoxicity to FLT3-ITD cells. In a human FLT3+AML xenograft mouse model, FLT3L CAR-T cells could significantly prolong the survival of mice. Furthermore, it was found that FLT3L CAR-T cells could activate the FLT3/ERK signaling pathway of FLT3+leukemia cells with wild-type FLT3; meanwhile, it had no inhibitory effects on the colony formation of CD34+stem cells derived from normal human umbilical cord blood.ConclusionsThe ligand-based FLT3L CAR-T cells could be a promising strategy for FLT3+AML treatment, especially those carried FLT3 mutation.
登录
查看更多内容
影响因子：
11.4
作者：
Kenderian SS;Ruella M;Shestova O;Klichinsky M;Aikawa V;Morrissette JJ;Scholler J;Song D;Porter DL;Carroll M;June CH;Gill S
通讯作者：
Gill S
影响因子：
4.5
作者：
Ma Q;Garber HR;Lu S;He H;Tallis E;Ding X;Sergeeva A;Wood MS;Dotti G;Salvado B;Ruisaard K;Clise-Dwyer K;John LS;Rezvani K;Alatrash G;Shpall EJ;Molldrem JJ
通讯作者：
Molldrem JJ
影响因子：
20.3
作者：
Kottaridis, PD;Gale, RE;Linch, DC
通讯作者：
Linch, DC
影响因子：
28.5
作者：
Lichtenegger FS;Krupka C;Haubner S;Köhnke T;Subklewe M
通讯作者：
Subklewe M
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA