工程化下一代 CAR-T 细胞：新型嵌合抗原受体变体设计与筛选的最新突破与遗留挑战

Chimeric antigen receptor (CAR) T cells are a powerful treatment against hematologic cancers. The functional phenotype of a CAR-T cell is influenced by the domains that comprise the synthetic receptor. Typically, the potency of therapeutic CAR-T cell candidates is assessed by preclinical functional assays and mouse models (i. e. human tumor xenografts).

However, to date, only a few sets of domains (e. g. CD8, CD28, 41BB) have been extensively tested in preclinical assays and human clinical studies. To characterize the efficiency of a CAR, different assays have been utilized to analyze T cell phenotypes, such as expansion, cytotoxicity, secretome, and persistence.

However, each of these previous studies evaluated the importance of an assay differently, resulting in a wide range of functionally diverse CARs. In this review, we highlight recent (high-throughput) methods to analyze CAR domains and demonstrate their impact on inducing T cell phenotypes and activity.

We also describe advances in computational methods and their potential for identifying CAR variants with enhanced properties.

Finally, we reflect on the need for a standardized scoring system to support the clinical development of next-generation CARs.