Supplementary Material for: Cellular Immunotherapy in B-Cell Malignancy

In recent years, cellular immunotherapy in B-cell malignancies has been driven by adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs). CARs consist of a single chain variable fragment (scFv) of a monoclonal antibody, a spacer domain, a transmembrane domain, an intracellular signaling domain, and additional costimulatory domains. The bulk of clinical data available is on CD19-targeting CAR T cells for the treatment of B-cell acute lymphocytic leukemia (B-ALL), chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma. Results so far have been promising with impressive rates and depth of remission especially among B-ALL patients. However, CAR T-cell therapy is a complex multi-step process, and clinical trials so far differ profoundly in CAR construct used, gene transfer method, composition of the cellular product, lymphodepletion, and CAR T-cell dose used. Randomized trials will be needed to conclusively evaluate the implications of these differences. The treatment concept is associated with significant neurotoxicity and potentially lethal cytokine release syndrome, both of which require specific management. Improvements in CAR design may help to overcome toxicity, the effects of an immunosuppressive microenvironment, and tumor escape by development of antigen-negative clones. This review will explain the mechanism of action, summarize the clinical experience with this treatment modality so far, and explore future developments in the field.

近年来，B细胞恶性肿瘤领域的细胞免疫治疗，主要依托于表达嵌合抗原受体（chimeric antigen receptors，CARs）的基因工程改造T细胞的过继转移。CARs由单克隆抗体的单链可变区片段（single chain variable fragment，scFv）、分隔结构域、跨膜结构域、胞内信号结构域以及额外的共刺激结构域组成。目前已有的大量临床数据均聚焦于靶向CD19的CAR-T细胞，用于治疗B细胞急性淋巴细胞白血病（B-cell acute lymphocytic leukemia，B-ALL）、慢性淋巴细胞白血病及B细胞非霍奇金淋巴瘤。迄今为止的治疗结果令人鼓舞，患者可获得可观的缓解率与缓解深度，在B-ALL患者中尤为显著。然而，CAR-T细胞治疗是一套复杂的多步骤流程，目前已开展的临床试验在所用CAR构建体、基因转导方法、细胞产物组成、淋巴细胞清除方案以及CAR-T细胞给药剂量等方面均存在显著差异。未来需开展随机对照试验，以明确评估这些差异所带来的临床影响。该治疗方案伴随显著的神经毒性以及潜在致命性的细胞因子释放综合征，二者均需针对性的干预措施。CAR设计的优化或可帮助克服治疗相关毒性、免疫抑制性肿瘤微环境的负面影响，以及抗原阴性克隆介导的肿瘤逃逸。本综述将阐释CAR-T细胞治疗的作用机制，总结该治疗手段迄今的临床应用经验，并探讨该领域的未来发展方向。