肿瘤细胞治疗研究
英文原题：Development of CAR T cells Targeting a Surface RNA Binding Protein for the Treatment of Acute Leukemias.
开发用于急性髓系白血病（AML）的嵌合抗原受体（CAR）T细胞一直充满挑战，原因是缺乏已知的、能够不伤及正常造血前体细胞的AML相关抗原。
开发用于急性髓系白血病（AML）的嵌合抗原受体（CAR）T细胞一直面临挑战，原因在于缺乏已知的AML相关抗原，而这些抗原需不损伤正常造血前体细胞。在此，我们推测，来自经异基因移植治愈的AML受者、并介导移植物抗白血病效应的供者自身抗体，可被改造以构建有效的CAR-T细胞。我们针对其中一个此类抗原——U5 snRNP200——生成了CAR-T细胞；U5 snRNP200是一种RNA解旋酶，定位于AML细胞表面，而不存在于正常造血前体细胞。抗U5 snRNP200 CAR-T细胞在AML的人源及同基因模型中均有效，在B细胞急性淋巴细胞白血病（B-ALL）中亦有效，后者同样存在表面U5 snRNP200。用IL-18武装CAR-T细胞后，可导致AML抗原表达增加、持久缓解，并免受AML再次攻击。这些数据由此确定了一个CAR-T细胞平台，该平台解决了此前在肿瘤选择性方面以及急性白血病患者安全性方面的局限。
Developing chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells. Here we reasoned that donor autoantibodies from AML recipients cured following allogeneic transplant and responsible for graft-versus-leukemia effect could be engineered to create effective CAR-T cells. We generated CAR-T cells against one such antigen - U5 snRNP200, an RNA helicase localized to the AML cell surface and absent from normal hematopoietic precursors. Anti-U5 snRNP200 CAR-T cells were effective in human and syngeneic models of AML as well as B-cell acute lymphoblastic leukemia (B-ALL), a setting where surface U5 snRNP200 is also present. Armoring CAR-T cells with IL-18 led to antigen gain on AML, durable remission, and protection from AML rechallenge. These data thereby identify a CAR-T cell platform which addresses prior limitations in tumor-selectivity and safety for patients with acute leukemias.
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