T cells genetically engineered to express chimeric antigen receptors (CARs) have proven - and impressive - therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. Nevertheless, various barriers restrict the efficacy and/or prevent the widespread use of CAR T cell therapies in these patients as well as in those with other cancers, particularly solid tumours. Key challenges relating to CAR T cells include severe toxicities, restricted trafficking to, infiltration into and activation within tumours, suboptimal persistence in vivo, antigen escape and heterogeneity, and manufacturing issues. The evolution of CAR designs beyond the conventional structures will be necessary to address these limitations and to expand the use of CAR T cells to a wider range of malignancies. Investigators are addressing the current obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. In this Review, we discuss the innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with diverse cancers.

中文翻译：

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克服当前 CAR T 细胞治疗障碍的工程策略。

经基因工程改造以表达嵌合抗原受体 (CARs) 的 T 细胞已在患有某些 B 细胞白血病或淋巴瘤亚型的患者中证明了 - 并且令人印象深刻 - 治疗活性，并且在多发性骨髓瘤患者中也证明了有希望的疗效。然而，各种障碍限制了 CAR T 细胞疗法在这些患者以及其他癌症患者（尤其是实体瘤患者）中的疗效和/或阻止其广泛使用。与 CAR T 细胞相关的主要挑战包括严重的毒性、限制运输、肿瘤浸润和激活、体内持久性不佳、抗原逃逸和异质性以及制造问题。CAR 设计超越传统结构的发展对于解决这些限制并将 CAR T 细胞的使用扩展到更广泛的恶性肿瘤是必要的。研究人员正在通过广泛的工程策略解决当前的障碍，以提高这种治疗方式的安全性、有效性和适用性。在这篇综述中，我们讨论了正在开发的新型 CAR T 细胞产品的创新设计，以增加和扩大这些治疗在多种癌症患者中的临床益处。