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CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.
Leukemia ( IF 12.8 ) Pub Date : 2020-03-24 , DOI: 10.1038/s41375-020-0792-2
Kristen Fousek 1, 2, 3, 4 , Junji Watanabe 5 , Sujith K Joseph 2, 3, 4 , Ann George 5 , Xingyue An 6 , Tiara T Byrd 1, 2, 3, 4 , Jessica S Morris 1, 2, 3, 4 , Annie Luong 5, 7 , Melisa A Martínez-Paniagua 6 , Khaled Sanber 2, 3, 4 , Shoba A Navai 2, 3, 4 , Ahmed Z Gad 1, 2, 3, 4 , Vita S Salsman 2, 3, 4 , Pretty R Mathew 2, 3, 4 , Hye Na Kim 5, 7 , Dimitrios L Wagner 2, 8, 9 , Lorenzo Brunetti 2 , Albert Jang 2 , Matthew L Baker 10 , Navin Varadarajan 6 , Meenakshi Hegde 2, 3, 4 , Yong-Mi Kim 5, 7 , Nora Heisterkamp 5, 7, 11 , Hisham Abdel-Azim 5, 7 , Nabil Ahmed 1, 2, 3, 4
Affiliation  

Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(-) disease. We report that CD19(-) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(-) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(-) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.

中文翻译:

无论 CD19 表达如何,靶向急性 B 系白血病的 CAR T 细胞。

靶向 CD19 的嵌合抗原受体 (CAR) T 细胞在治疗 B 系急性淋巴细胞白血病 (BL-ALL) 方面表现出显着疗效,但高达 39% 的治疗患者复发 CD19(-) 疾病。我们报告CD19(-) 逃逸与下调,但保存,CD20 和CD22 的靶向表达有关。因此,我们推断扩大 CD19CAR T 细胞谱以包括 CD20 和 CD22 将使它们能够靶向 CD19(-) 逃避 BL-ALL,同时保持其前期功效。我们通过使用一个三顺反子转基因在单个 T 细胞上共表达单个 CAR 分子,创建了一个 CD19/20/22 靶向 CAR T 细胞。在体外和动物模型中,CD19/20/22CAR T 细胞杀死了 CD19CAR T 细胞治疗和 CRISPR/Cas9 CD19 敲除原发性 BL-ALL 后复发的患者的 CD19(-) 原始细胞,而CD19CAR T细胞无效。在亚细胞水平上,CD19/20/22CAR T 细胞与靶细胞形成致密的免疫突触,介导有效的溶细胞复合物形成,在单细胞追踪研究中是有效的连环杀手,并且与 CD19CAR T 细胞对抗原发性 CD19 一样有效(+) 疾病。总之,独立于 CD19 表达,CD19/20/22CAR T 细胞可用作顽固性疾病患者的抢救或一线 CAR 治疗。
更新日期:2020-04-24
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