针对 FLT3 中反复驱动突变的 T 细胞受体介导体内原发性人类急性髓系白血病的消除。
A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.
发表日期：2023 Oct 02
作者：
Eirini Giannakopoulou, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Yingqian Li, Terhi Karpanen, Tetsuichi Yoshizato, Even H Rustad, Morten Milek Nielsen, Ravi Chand Bollineni, Trung T Tran, Marina Delic-Sarac, Thea Johanne Gjerdingen, Karolos Douvlataniotis, Maarja Laos, Muhammad Ali, Amy Hillen, Stefania Mazzi, Desmond Wai Loon Chin, Adi Mehta, Jeppe Sejerø Holm, Amalie Kai Bentzen, Marie Bill, Marieke Griffioen, Tobias Gedde-Dahl, Sören Lehmann, Sten Eirik W Jacobsen, Petter S Woll, Johanna Olweus
来源：
Nature Cancer
摘要：
急性髓系白血病 (AML) 是成人中最常见的白血病，是由有限数量的基因中反复出现的体细胞获得性遗传损伤引起的。酪氨酸激酶抑制剂治疗已证明，尽管 FLT3 抑制剂消除 FLT3 突变克隆的功效存在差异，但针对常见的 FMS 相关受体酪氨酸激酶 3 (FLT3) 功能获得性突变的靶向治疗可为患者带来显着的生存获益。我们鉴定了一种 T 细胞受体 (TCR)，它对 FLT3 酪氨酸激酶结构域 (TCRFLT3D/Y) 中反复出现的 D835Y 驱动突变有反应。 TCRFLT3D/Y 重定向 T 细胞在体外和体内选择性消除含有 FLT3D835Y 突变的原代人类 AML 细胞。在移植了来自患者的原发性白血病的小鼠中，TCRFLT3D/Y细胞排斥CD34和CD34-AML，达到最小残留疾病阴性水平，并消除体内原发性CD34 AML白血病增殖细胞。因此，针对单一共享突变的 T 细胞可以提供有效的免疫疗法，选择性消除体内涉及克隆的原代 AML 细胞。© 2023。作者。
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 (TCRFLT3D/Y). TCRFLT3D/Y-redirected T cells selectively eliminated primary human AML cells harboring the FLT3D835Y mutation in vitro and in vivo. TCRFLT3D/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.© 2023. The Author(s).