A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies
A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies
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DOI：
10.1182/blood-2015-02-629527
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发表时间：
2015-08-20
期刊：
影响因子：
20.3
通讯作者：
Brenner, Malcolm K.
中科院分区：
文献类型：
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作者：
Mamonkin, Maksim;Rouce, Rayne H.;Brenner, Malcolm K.
T细胞恶性肿瘤的靶向治疗方案仍然稀缺。近期的临床试验表明，嵌合抗原受体（CAR）能够有效地重定向T淋巴细胞以根除B细胞来源的淋巴恶性肿瘤。然而，由于正常T细胞和恶性T细胞之间大多数可靶向的表面抗原存在共同表达，T系肿瘤对于CAR - T细胞来说仍然是一项更具挑战性的任务，这可能导致CAR - T细胞的自相残杀或严重的免疫缺陷。在此，我们报道用一种靶向CD5（正常和肿瘤性T细胞的一种常见表面标志物）的CAR转导的T细胞仅发生有限的自相残杀，并且能够在体外长期扩增。这些CD5 CAR - T细胞在体外能有效清除恶性T细胞急性淋巴细胞白血病（T - ALL）和T细胞淋巴瘤细胞系，并在T - ALL异种移植小鼠模型中显著抑制疾病进展。这些数据支持了CD5 CAR在T细胞肿瘤患者中的治疗潜力。
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.