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Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma

嵌合抗原受体 T 细胞在治疗难治/复发多发性骨髓瘤中的新进展

Abstract

multiple myeloma (MM), considered an incurable hematological malignancy, is characterized by its clonal evolution of malignant plasma cells. Although the application of autologous stem cell transplantation (ASCT) and the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have doubled the median overall survival to eight years, relapsed and refractory diseases are still frequent events in the course of MM. To achieve a durable and deep remission, immunotherapy modalities have been developed for relapsed/refractory multiple myeloma (RRMM). Among these approaches, chimeric antigen receptor (CAR) T-cell therapy is the most promising star, based on the results of previous success in B-cell neoplasms. In this immunotherapy, autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure. Tisagenlecleucel and Axicabtagene, targeting the CD19 antigen, are the two pacesetters of CAR T-cell products. They were approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Their development enabled unparalleled efficacy in combating hematopoietic neoplasms. In this review article, we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.

概要

多发性骨髓瘤被认为是一种无法治愈的血液系统恶性疾病, 其特征为恶性浆细胞的克隆性增殖. 尽管在过去的几十年中, 自体干细胞移植 (ASCT) 的应用及新型药物 (蛋白酶体抑制剂和免疫调节药) 的问世, 将患者的中位生存时间由原来的 4 年提高到了 8 年, 但复发与难治仍然是多发性骨髓瘤疾病进程中难以逾越的鸿沟. 为了获得长期持续的缓解, 免疫治疗开始在多发性骨髓瘤中崭露头角, 其中嵌合抗原受体 (CAR) T 细胞治疗就是最有潜力的一颗新星. 通过在基因层面改造患者自己的 T 细胞, 使 T 细胞表达一种特定的受体 (人造的融合蛋白), 该受体可以识别并结合肿瘤相关抗原, 并活化 T 细胞启动后续的杀伤过程. Tisagenlecleucel 和 Axicabtagene 是两个针对 CD19 抗原的 CAR T 产品, 用于治疗 B 细胞来源的急性淋巴细胞白血病 (B-ALL) 和弥漫大 B 细胞淋巴瘤 (DLBCL), 并于 2017 年被美国食品药品监督管理局 (FDA)批准. 这两个产品的发展极大推动了 B 细胞来源的恶性血液系统疾病的治疗, 并刷新了对于传统治疗的认知. 基于之前 CAR T 治疗的成功经验, 寻找如 CD19 一样的特定靶点能为 CAR T 治疗多发性骨髓瘤打下基础. 本综述介绍了数个在骨髓瘤细胞上的肿瘤靶抗原, 如 B 细胞成熟抗原 (BCMA) 和 CD38. 这些针对抗原的 CAR T 治疗有些还在实验室阶段, 而有些已经进入了 3 期的临床试验, 很有可能成为下一个被批准的 CAR T 产品. 另外, 本综述也介绍了在 CAR T 治疗中出现的毒副反应以及相应的管理和处理方法.

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He HUANG took the lead in writing the manuscript. Heng-wei WU wrote and edited the manuscript. Yong-xian HU contributed to shaping the tables and figures. All authors read and approved the final manuscript and, therefore, had full access to all the data in the study and take responsibility for the integrity and security of the data.

Correspondence to He Huang.

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He HUANG, Heng-wei WU, and Yong-xian HU declare that they have no conflict of interest.

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Huang, H., Wu, H. & Hu, Y. Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma. J. Zhejiang Univ. Sci. B 21, 29–41 (2020). https://doi.org/10.1631/jzus.B1900351

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Key words

  • Chimeric antigen receptor (CAR) T cells
  • Immunotherapy
  • Monoclonal antibody (mAb)
  • Target antigen
  • Multiple myeloma

关键词

  • 嵌合抗原受体 (CAR) T 细胞
  • 免疫治疗
  • 单克隆抗体
  • 靶抗原
  • 多发性骨髓瘤

CLC number

  • R733.3