嵌合抗原受体介导的T细胞选择性治疗T细胞恶性肿瘤

icartab

A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies

Key Points

· T cells transduced with a CD5 CAR demonstrate limited and transient fratricide and expand ex vivo.

· CD5 CAR T cells eliminate T-ALL blasts in vitro and control disease progression in xenograft T-ALL mouse models.

· Abstract

Options for targeted therapy of T-cell malignancies remain scarce. Recent clinical trials demonstrated that chimeric antigen receptors (CARs) can effectively redirect T lymphocytes to eradicate lymphoid malignancies of B-cell origin. However, T-lineage neoplasms remain a more challenging task for CAR T cells due to shared expression of most targetable surface antigens between normal and malignant T cells, potentially leading to fratricide of CAR T cells or profound immunodeficiency. Here, we report that T cells transduced with a CAR targeting CD5, a common surface marker of normal and neoplastic T cells, undergo only limited fratricide and can be expanded long-term ex vivo. These CD5 CAR T cells effectively eliminate malignant T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma lines in vitro and significantly inhibit disease progression in xenograft mouse models of T-ALL. These data support the therapeutic potential of CD5 CAR in patients with T-cell neoplasms.

· Submitted February 17, 2015.

· Accepted June 3, 2015.

· © 2015 by The American Society of Hematology

嵌合抗原受体介导的T细胞选择性治疗T细胞恶性肿瘤

关键观点:

l 转导CD5的嵌合抗原受体修饰的T细胞展现了有限和短暂的自相残杀能力，以及体外扩增能力。

l CD5 CAR-T细胞在体外消除T-ALL疾病爆发和控制异种移植小鼠模型体内的T-ALL

摘要：

针对T细胞恶性肿瘤的靶向治疗方案仍然很稀缺。最近的临床试验表明，嵌合抗原受体（CARs）可以有效地重新定向T淋巴细胞，并消除B细胞起源的恶性淋巴细胞。然而，T系肿瘤仍然是一个更具挑战性的任务，因为它表达大多数的正常细胞和恶性T细胞表面共同的抗原，可能会导致CAR-T细胞相互残杀或者影响较大的免疫缺陷。此文中，我们报道了T细胞转导了一个嵌合抗原受体CD5（一个普通的正常或者T细胞肿瘤的表面标记物）会导致有限的自相残杀能力并且能够长期在体外进行扩增。这些CD5修饰的CAR-T细胞能够有效地在体外消除恶性T细胞急性淋巴细胞白血病（T-ALL）和T细胞淋巴瘤系，并能在T-ALL异种移植小鼠模型体内显著的限制疾病的进程。这些数据证明CD5 CAR-T在T细胞肿瘤病人体内会有治疗的潜能。

提交2015年2月17日。

2015年6月3日接受。

©2015由美国血液学会

出自爱康得