肿瘤细胞治疗研究
英文原题：A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.
急性髓系白血病（AML）是成人中最常见的白血病，由有限数量的基因中反复发生的体细胞获得性遗传损伤驱动。
急性髓系白血病（AML）是成人中最常见的白血病，由有限数量基因中反复发生的体细胞获得性遗传病变驱动。酪氨酸激酶抑制剂治疗已证明，靶向常见的FMS相关受体酪氨酸激酶3（FLT3）功能获得性突变可为患者提供显著的生存获益，尽管FLT3抑制剂在消除FLT3突变克隆方面的疗效不一。我们鉴定了一种对FLT3酪氨酸激酶结构域中反复出现的D835Y驱动突变具有反应性的T细胞受体（TCR）（TCR FLT3D/Y）。TCR FLT3D/Y重定向的T细胞在体外和体内选择性消除了携带FLT3 D835Y突变的原代人AML细胞。TCR FLT3D/Y细胞在移植了患者原代白血病的小鼠中排斥了CD34+和CD34- AML，达到微小残留病阴性水平，并在体内消除了原代CD34+ AML白血病增殖细胞。因此，靶向单一共享突变的T细胞可提供有效的免疫治疗，以在体内选择性消除克隆性受累的原代AML细胞。
Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCR FLT3D/Y ). TCR FLT3D/Y -redirected T cells selectively eliminated primary human AML cells harboring the FLT3 D835Y mutation in vitro and in vivo. TCR FLT3D/Y cells rejected both CD34 + and CD34 - AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34 + AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.
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