CS1-BCMA双靶CAR-T细胞治疗多发性骨髓瘤的研究进展

胡豫; 梅恒; 李成功

doi:10.13201/j.issn.1004-2806.2024.07.002

CS1-BCMA双靶CAR-T细胞治疗多发性骨髓瘤的研究进展

- 1.
  华中科技大学同济医学院附属协和医院血液病研究所(武汉，430022)
- 2.
  湖北省肿瘤疾病细胞治疗临床医学研究中心

详细信息

作者简介:
胡豫，医学博士、教授、主任医师、博士生导师，华中科技大学同济医学院附属协和医院院长，教育部生物靶向治疗重点实验室主任，华中科技大学血液病学研究所所长。国家杰出青年科学基金获得者、国家科技进步二等奖获得者、全国创新争先奖章获得者、“长江学者”特聘教授、全国教书育人楷模获得者、全国优秀医院院长获得者、何梁何利基金奖获得者、中国医院管理突出贡献奖获得者。担任中华医学会血液学分会候任主委、中华医学会内科学分会副主委、中国医师协会血液科医师分会副会长、中国医院协会副会长、中国病理生理学会实验血液学会副主委、国际血栓与止血学会教育委员会委员。担任本专业国际刊物Thrombosis Research、Thrombosis and Haemostasis副主编，《临床内科杂志》《临床血液学杂志》《临床急诊杂志》主编、《中华血液学杂志》《中国医院管理》副主编、《中华医院管理杂志》编委等。从事血液病医疗工作30余年，主持临床一线工作。在各种疑难血液病的临床诊治方面具有丰富经验，特别是对出凝血疾病如难治免疫性血小板减少症、易栓症，恶性血液疾病如多发性骨髓瘤等方面具有较深造诣

通讯作者: 胡豫，E-mail：dr_huyu@126.com

中图分类号: R733.3

收稿日期: 2024-06-04

刊出日期: 2024-07-01

Research advance of CS1-BCMA bispecific CAR-T cell therapy in multiple myeloma

- 1.
  Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- 2.
  Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease

More Information

Corresponding author: HU Yu, E-mail: dr_huyu@126.com

Received Date: 04 June 2024

Publish Date: 01 July 2024

摘要

摘要: 在难治/复发多发性骨髓瘤(refractory/relapsed multiple myeloma，RRMM)中，嵌合抗原受体T细胞(chimeric antigen receptor-T，CAR-T)治疗代表了一项重大的科学进步，对许多患者来说，具有高反应率和长期缓解。尽管如此，肿瘤细胞表面靶抗原下调可导致反应较差和疾病复发。目前获批用于治疗RRMM的CAR-T细胞疗法仅针对B细胞成熟抗原(B cell maturation antigen，BCMA)。虽然BCMA-CAR-T细胞治疗的反应率高，但其对靶抗原的选择性压力可引起BCMA表达丢失和MM细胞逃逸。双靶CAR-T细胞理论上具有靶向性更广和减轻单靶逃逸的优势。BCMA和CS1在MM细胞上高表达，被认为是MM免疫治疗的理想靶点。文章总结了商品化BCMA-CAR-T细胞治疗RRMM和CS1-CAR-T细胞治疗MM的研究进展，并重点讨论了CS1-BCMA CAR-T细胞治疗的早期试验结果。
- 多发性骨髓瘤 /
- 嵌合抗原受体T细胞治疗 /
- B细胞成熟抗原 /
- CS1 /
- 双靶
Abstract: In refractory/relapsed multiple myeloma(RRMM), chimeric antigen receptor-T(CAR-T) cell therapy represents a significant scientific advancement, with high response rates and long-term remission for many patients. However, target antigen downregulation on tumor cells can lead to poor response and disease recurrence. Currently, CAR-T cell therapy approved for the treatment of RRMM only targets B cell maturation antigen(BCMA). Although BCMA-CAR-T cell therapy has a high response rate, its selective pressure on target antigens can cause BCMA loss and MM escape. Bispecific CAR-T cells theoretically have the advantages of broader targeting and less single-target escape. BCMA and CS1 are highly expressed on MM cells and are considered ideal targets for MM immunotherapy. This review summarizes the research progress of commercial BCMA-CAR-T cell therapy for RRMM and CS1-CAR-T cell therapy for MM and focuses on the primary results of CS1-BCMA CAR-T cells.
- multiple myeloma /
- chimeric antigen receptor-T cell therapy /
- B cell maturation antigen /
- CS1 /
- bispecific

HTML全文

表 1 CS1-CAR-T和CS1-BCMA CAR-T细胞治疗MM的研究进展

CS1-CAR设计	载体	T细胞	体外研究	体内研究	靶向脱靶毒性	参考文献
CS1 scFv来自杂交瘤细胞，CD28为共刺激结构域，CD3ζ为胞内区	Pinco 逆转录病毒	健康供者 T细胞	NCI-H929, IM9， MM.1S，RPMI-8226，原代MM细胞	MM.1S和IM9 小鼠模型	未评估	^[27]
靶向CS1远端可变区的Luc90-scFv，CD28和4-1BB为共刺激结构域，CD3ζ为胞内区	慢病毒	健康供者 T细胞	MM.1S，CS1-KD MM.1S，原代MM 细胞	MM.1S和OPM2 小鼠模型	CD8⁺CAR-T 细胞自绞杀，敲除CS1可缓解	^[28]
Luc63-scFv，CD28为共刺激结构域，CD3ζ为胞内区	epHIV7 慢病毒	健康供者 T细胞	NCI-H929，OPM2， MM.1S，CS1-K562，原代MM细胞	MM.1s小鼠模型	选择性杀伤 CS1^+/high淋巴细胞	^[29]
Luc90-scFv和Luc63-scFv，CD28为共刺激结构域，CD3ζ为胞内区，iCasp9自杀基因	Gamma 逆转录病毒	健康供者 T细胞	CS1-RPMI-8226， CS1-K562，MM.1S，原代MM细胞	MM.1S的局部肿瘤和全身肿瘤小鼠模型	CD8⁺CAR-T 细胞自绞杀，不影响CAR-T 细胞扩增	^[30]
靶向CS1的scFv，CD28为共刺激结构域，CD3ζζ为胞内区	pHIV7 慢病毒	健康供者 T细胞	KG1a，MM.1R， MM.1S，U266B， LCL OKT3	MM.1S小鼠模型	未评估	^[31]
靶向CS1的scFv	未报道	TALEN技术敲除健康供者T细胞的TRAC和 CS1基因	MM.1S，原代MM 细胞	原代MM细胞的 PDX小鼠模型	对外周血单个核细胞和造血干细胞无杀伤	^[32]
靶向CS1的scFv	未报道	TALEN技术敲除健康供者T细胞的TRAC和 CS1基因	MM.1S，L363，UM9， U266，原代MM细胞	MM小鼠模型	未评估	^[33]
BCMA-scFv-4-1BB-CD3ζ和CS1-scFv-4-1BB-CD3ζ以P2A连接	慢病毒	健康供者 T细胞	MM.1S，RPMI-8226， U266，原代MM细胞	MM.1S小鼠模型， K562-CS1和 K562-BCMA混合和单独小鼠模型	未评估	^[34]
Luc63-scFv-cBCMA-scFv(11D5.3)，4-1BB为共刺激结构域，CD3ζ为胞内区	逆转录病毒	健康供者 T细胞	BCMA⁺/CS1^-MM.1S， BCMA^-/CS1⁺MM.1S， BCMA⁺/CS1⁺MM.1S	BCMA⁺/CS1⁺， BCMA⁺/CS1^-和 BCMA^-/CS1⁺MM.1S 1∶1∶1小鼠模型	对CD8⁺ T细胞无杀伤	^[35]
CS1-scFv(7A8D5)-BCMA-scFv，4-1BB为共刺激结构域，CD3ζ为胞内区	慢病毒	健康供者 T细胞	MM.1S，CHO-BCMA， CHO-CS1	MM.1S小鼠模型	未评估	^[36]

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