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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。
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关键词:
- 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. -
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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 OKT3MM.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.1SBCMA+/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-CS1MM.1S小鼠模型 未评估 [36] 
下载: 导出CSV
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| 引用本文: |
胡豫, 梅恒, 李成功. CS1-BCMA双靶CAR-T细胞治疗多发性骨髓瘤的研究进展[J]. 临床血液学杂志, 2024, 37(7): 446-452. doi: 10.13201/j.issn.1004-2806.2024.07.002
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| Citation: |
HU Yu, MEI Heng, LI Chenggong. Research advance of CS1-BCMA bispecific CAR-T cell therapy in multiple myeloma[J]. J Clin Hematol, 2024, 37(7): 446-452. doi: 10.13201/j.issn.1004-2806.2024.07.002
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