Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia
Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia
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DOI：
10.1182/blood.2019002779
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发表时间：
2020-03-05
期刊：
影响因子：
20.3
通讯作者：
Hua, Xianxin
中科院分区：
文献类型：
--
作者：
He, Xin;Feng, Zijie;Hua, Xianxin
嵌合抗原受体（CAR）T细胞通过靶向CD 19从根本上改善了B细胞来源的恶性肿瘤的治疗。这种成功尚未扩大到治疗急性髓细胞白血病（AML）。我们开发了一种顺序肿瘤选择性抗体和抗原修复（星星）系统，以快速分离优先结合AML细胞并赋予CAR T细胞抗AML功效的多个纳米抗体（Nbs）。STAR分离的Nb157特异性结合在AML细胞中高度表达的CD13，并且CD13 CAR T细胞在体外和体内有效消除AML。CAR T细胞对AML白血病干细胞中上调的CD13和TIM 3具有双特异性，根除了患者来源的AML，对小鼠模型中的人骨髓干细胞和外周骨髓细胞的毒性大大降低，突出了开发有效AML CAR T细胞疗法的有希望的方法。
Chimeric antigen receptor (CAR) T cells have radically improved the treatment of B cell-derived malignancies by targeting CD19. The success has not yet expanded to treat acute myeloid leukemia (AML). We developed a Sequentially Tumor-Selected Antibody and Antigen Retrieval (STAR) system to rapidly isolate multiple nanobodies (Nbs) that preferentially bind AML cells and empower CAR T cells with anti-AML efficacy. STAR-isolated Nb157 specifically bound CD13, which is highly expressed in AML cells, and CD13 CAR T cells potently eliminated AML in vitro and in vivo. CAR T cells bispecific for CD13 and TIM3, which are upregulated in AML leukemia stem cells, eradicated patient-derived AML, with much reduced toxicity to human bone marrow stem cells and peripheral myeloid cells in mouse models, highlighting a promising approach for developing effective AML CAR T cell therapy.