CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.,Leukemia

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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

Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Division of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA, United States.
Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.
University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Institute of Medical Immunology, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Berlin Institute of Health-Center for Regenerative Therapies (B-CRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
National Center for Macromolecular Imaging and Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Department of Systems Biology, Beckman Research Institute City of Hope, Duarte, CA, United States.

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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