Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA; email:
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
Annu Rev Chem Biomol Eng. 2022 Jun 10;13:193-216. doi: 10.1146/annurev-chembioeng-092120-092914.
T cells engineered to express chimeric antigen receptors (CARs) have shown remarkable success in treating B-cell malignancies, reflected by multiple US Food and Drug Administration-approved CAR-T cell products currently on the market. However, various obstacles have thus far limited the use of approved products and constrained the efficacy of CAR-T cell therapy against solid tumors. Overcoming these obstacles will necessitate multidimensional CAR-T cell engineering approaches and better understanding of the intricate tumor microenvironment (TME). Key challenges include treatment-related toxicity, antigen escape and heterogeneity, and the highly immunosuppressive profile of the TME. Notably, the hypoxic and nutrient-deprived nature of the TME severely attenuates CAR-T cell fitness and efficacy, highlighting the need for more sophisticated engineering strategies. In this review, we examine recent advances in protein- and cell-engineering strategies to improve CAR-T cell safety and efficacy, with an emphasis on overcoming immunosuppression induced by tumor metabolism and hypoxia.
经基因工程改造表达嵌合抗原受体 (CAR) 的 T 细胞在治疗 B 细胞恶性肿瘤方面取得了显著成功，这反映在多个已获得美国食品和药物管理局批准的 CAR-T 细胞产品上。然而，各种障碍迄今为止限制了已批准产品的使用，并限制了 CAR-T 细胞疗法对实体瘤的疗效。克服这些障碍将需要多维的 CAR-T 细胞工程方法和对复杂的肿瘤微环境 (TME) 的更好理解。主要挑战包括与治疗相关的毒性、抗原逃逸和异质性，以及 TME 的高度免疫抑制特征。值得注意的是，TME 的缺氧和营养缺乏性质严重削弱了 CAR-T 细胞的适应性和疗效，这凸显了需要更复杂的工程策略。在这篇综述中，我们研究了提高 CAR-T 细胞安全性和疗效的蛋白质和细胞工程策略的最新进展，重点是克服肿瘤代谢和缺氧诱导的免疫抑制。
