In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL.
In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL.
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DOI：
10.1158/1535-7163.mct-20-1089
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发表时间：
2021-07
影响因子：
5.7
通讯作者：
O'Connor RS
中科院分区：
文献类型：
--
作者：
Safarzadeh Kozani P;Safarzadeh Kozani P;O'Connor RS
将合成生物学与过继性T细胞转移相结合，在治疗复发性难治性B细胞急性淋巴细胞白血病（R/R B-ALL）、弥漫性大B细胞淋巴瘤（DLBCL）和套细胞淋巴瘤（MCL）方面取得了可喜的进展。嵌合抗原受体（汽车）是重定向针对癌症的T细胞特异性的合成受体。汽车包括“内置”信号传导结构域，其重新编程T细胞代谢，增强效应子功能，并支持长期持久性。尽管它们在血液恶性肿瘤中取得了成功，但由于几个原因，CD 19重定向的CAR T细胞疗法可能会发生复发，包括植入不良，体内增殖受损和T细胞衰老。在此，我们解释了CAR设计中的细微变化如何克服有效过继免疫治疗的障碍。我们还讨论了单链可变片段（scFv）的理化性质如何影响分化和持久性。此外，我们描述了CAR工程的创新进展，并提供了对人源化scFv的开发的见解，其建议的益处包括增加的持久性和改善的临床结果。由于CD 19阴性白血病细胞亚群的出现或存在，肿瘤细胞可以逃避检测和CAR介导的消除。我们讨论了靶向其他B-ALL相关抗原的机会和挑战。确定替代靶点对于恢复CAR T细胞疗法在CD 19阴性B-ALL患者中的成功至关重要。
Combining synthetic biology with adoptive T cell transfer has led to promising advances in the treatment of relapsed refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Chimeric antigen receptors (CARs) are synthetic receptors that redirect T cell specificity against cancer. CARs include “built-in” signaling domains that reprogram T cell metabolism, enhance effector function, and support long-term persistence. Despite their success in blood-based malignancies, relapse can occur in CD19-redirected CAR T cell therapies for several reasons including poor engraftment, impaired in vivo proliferation, and T cell senescence. Herein, we explain how subtle alterations in CAR design may overcome barriers to effective adoptive immunotherapy. We also discuss how the physiochemical properties of the single-chain variable fragment (scFv) impact differentiation and persistence. Moreover, we describe innovative advances in CAR engineering and provide insight into the development of humanized scFvs whose proposed benefits include increased persistence and improved clinical outcomes. Tumor cells can evade detection and CAR-mediated elimination due to the emergence or presence of CD19-negative leukemic cell subpopulations. We discuss the opportunities and challenges in targeting other B-ALL-associated antigens. Identifying alternate targets is fundamentally necessary to restore the success of CAR T-cell therapies in CD19-negative B-ALL patients.