A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML
A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML
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DOI：
10.1016/j.ymthe.2018.08.001
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发表时间：
2018-10-03
影响因子：
12.4
通讯作者：
Zhang, Cheng Cheng
中科院分区：
文献类型：
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作者：
John, Samuel;Chen, Heyu;Zhang, Cheng Cheng
为了有效改善急性髓细胞白血病（AML）的治疗，需要确定新的分子靶点和治疗方法。靶向肿瘤相关抗原的嵌合抗原受体（CAR）修饰的T细胞在治疗某些恶性肿瘤中显示出前景。然而，AML的CAR-T细胞开发受到缺乏对AML细胞具有高特异性的抗原的限制，该抗原不存在于正常造血干细胞上，因此不会导致骨髓毒性。在这里，我们证明，白细胞免疫球蛋白样受体-B4（LILRB 4）是一种肿瘤相关抗原高度表达的单核细胞AML细胞。我们产生了一种新的抗LILRB 4CAR-T细胞，其显示出高抗原亲和力和特异性。这些CAR-T细胞在体外和体内针对LILRB 4（+）AML细胞显示出有效的效应子功能。此外，我们证明了抗LILRB 4 CAR-T细胞在集落形成单位测定中对正常CD 34（+）脐带血细胞没有毒性，在人源化造血重建小鼠模型中也没有毒性。我们的数据表明，抗LILRB 4 CAR-T细胞特异性靶向单核细胞AML细胞，对正常造血祖细胞没有毒性。因此，这项工作提供了一种新的治疗策略，以改善单核细胞AML的结局，具有消除白血病疾病的潜力，同时最大限度地降低了靶向肿瘤外毒性的风险。
To effectively improve treatment for acute myeloid leukemia (AML), new molecular targets and therapeutic approaches need to be identified. Chimeric antigen receptor (CAR)-modified T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, CAR-T cell development for AML has been limited by lack of an antigen with high specificity for AML cells that is not present on normal hematopoietic stem cells, and thus will not result in myelotoxicity. Here we demonstrate that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. We generated a novel anti-LILRB4CAR-T cell that displays high antigen affinity and specificity. These CAR-T cells display efficient effector function in vitro and in vivo against LILRB4(+) AML cells. Furthermore, we demonstrate anti-LILRB4 CAR-T cells are not toxic to normal CD34(+) umbilical cord blood cells in colony-forming unit assays, nor in a humanized hematopoietic-reconstituted mouse model. Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic AML cells with no toxicity to normal hematopoietic progenitors. This work thus offers a new treatment strategy to improve outcomes for monocytic AML, with the potential for elimination of leukemic disease while minimizing the risk for on-target off-tumor toxicity.