van de Donk Niels W C J, Usmani Saad Z, Yong Kwee
Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
Lancet Haematol. 2021 Jun;8(6):e446-e461. doi: 10.1016/S2352-3026(21)00057-0.
Chimeric antigen receptors (CAR) are fusion proteins containing an antigen-recognition domain coupled to a T-cell activation domain (eg, CD3ζ [CD247]) and to a costimulatory domain (eg, CD28 or 4-1BB [TNFRSF9, also known as CD137]). The B-cell maturation antigen (BCMA; TNFRSF17) is an attractive target for CAR T-cell therapy because it is only expressed by normal and malignant plasma cells and by a subset of mature B cells. Several trials of anti-BCMA CAR T cells have shown high-quality responses, including minimal residual disease-negativity in patients with multiple myeloma who were heavily pretreated. Phase 3 trials are currently evaluating CAR T-cell therapy versus standard-of-care regimens in patients in earlier stages of the disease. Trials are also ongoing in newly diagnosed patients with high-risk cytogenetic profiles or with residual disease after transplantation. CAR T cells targeting other multiple myeloma antigens, such as CD19, CD38, CD138 (SYND1), and SLAMF7, are also being explored. Toxicities associated with CAR T cells include cytokine-release syndrome, different types of cytopenia, infections, and neurotoxicity. Although some subsets of patients have sustained responses for more than 1 year, most patients eventually relapse, which might be related to the loss of CAR T cells, loss of antigen expression on the tumour cell surface, or to an immunosuppressive microenvironment that impairs the activity of T cells. Efforts to improve the effectiveness of CAR T-cell therapy include optimising CAR design and adapting the manufacturing process to generate cell products enriched for specific subsets of T cells (eg, early memory cells). Other strategies explored in trials include dual-antigen targeting to prevent antigen escape and rational combination therapy to enhance persistence. Several approaches are also being developed to improve the safety of CAR T-cell therapy, such as the incorporation of a suicide gene safety system.
嵌合抗原受体（CAR）是一种融合蛋白，包含与T细胞激活域（如CD3ζ [CD247]）以及共刺激域（如CD28或4-1BB [TNFRSF9，也称为CD137]）偶联的抗原识别域。B细胞成熟抗原（BCMA；TNFRSF17）是CAR T细胞疗法的一个有吸引力的靶点，因为它仅在正常和恶性浆细胞以及一部分成熟B细胞中表达。多项抗BCMA CAR T细胞试验已显示出高质量的反应，包括在经过大量预处理的多发性骨髓瘤患者中实现微小残留病阴性。3期试验目前正在评估疾病早期患者接受CAR T细胞疗法与标准治疗方案的疗效对比。针对新诊断的具有高危细胞遗传学特征或移植后有残留病的患者的试验也在进行中。靶向其他多发性骨髓瘤抗原（如CD19、CD38、CD138 [SYND1]和信号淋巴细胞激活分子家族7 [SLAMF7]）的CAR T细胞也在探索中。与CAR T细胞相关的毒性包括细胞因子释放综合征、不同类型的血细胞减少、感染和神经毒性。尽管一些患者亚组有持续超过1年的反应，但大多数患者最终会复发，这可能与CAR T细胞的丧失、肿瘤细胞表面抗原表达的丧失或损害T细胞活性的免疫抑制微环境有关。提高CAR T细胞疗法有效性的努力包括优化CAR设计以及调整制造工艺以生产富含特定T细胞亚群（如早期记忆细胞）的细胞产品。试验中探索的其他策略包括双抗原靶向以防止抗原逃逸以及合理联合疗法以增强持久性。还在开发几种方法来提高CAR T细胞疗法的安全性，例如引入自杀基因安全系统。
