Aflac Cancer and Blood Disorders Center, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Cancer Biology Program, Graduate Division of Biological and Biomedical Sciences, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Cells. 2021 Dec 22;11(1):21. doi: 10.3390/cells11010021.
Chimeric antigen receptor (CAR) T-cell therapy has been widely successful in the treatment of B-cell malignancies, including B-cell lymphoma, mantle cell lymphoma, and multiple myeloma; and three generations of CAR designs have led to effective FDA approved therapeutics. Traditionally, CAR antigen specificity is derived from a monoclonal antibody where the variable heavy (V) and variable light (V) chains are connected by a peptide linker to form a single-chain variable fragment (scFv). While this provides a level of antigen specificity parallel to that of an antibody and has shown great success in the clinic, this design is not universally successful. For instance, issues of stability, immunogenicity, and antigen escape hinder the translational application of some CARs. As an alternative, natural receptor- or ligand-based designs may prove advantageous in some circumstances compared to scFv-based designs. Herein, the advantages and disadvantages of scFv-based and natural receptor- or ligand-based CAR designs are discussed. In addition, several translational aspects of natural receptor- and ligand-based CAR approaches that are being investigated in preclinical and clinical studies will be examined.
嵌合抗原受体 (CAR) T 细胞疗法在治疗 B 细胞恶性肿瘤方面已取得广泛成功，包括 B 细胞淋巴瘤、套细胞淋巴瘤和多发性骨髓瘤；三代 CAR 设计已产生有效的 FDA 批准疗法。传统上，CAR 抗原特异性源自单克隆抗体，其中可变重链 (V) 和可变轻链 (V) 通过肽接头连接，形成单链可变片段 (scFv)。虽然这种设计提供了与抗体平行的抗原特异性水平，并在临床中取得了巨大成功，但这种设计并非普遍成功。例如，稳定性、免疫原性和抗原逃逸问题阻碍了一些 CAR 的转化应用。作为替代方案，与 scFv 设计相比，天然受体或配体设计在某些情况下可能具有优势。本文讨论了基于 scFv 和天然受体或配体的 CAR 设计的优缺点。此外，还将研究正在临床前和临床研究中探索的基于天然受体和配体的 CAR 方法的几个转化方面。
