CAR-T细胞治疗自身免疫性疾病的研究述评

doi:10.3969/j.issn.1674-8115.2025.11.003

摘要/Abstract

摘要：

嵌合抗原受体T细胞（chimeric antigen receptor T cell，CAR-T细胞）治疗通过基因工程改造T细胞，使其能够特异性识别并高效清除靶细胞，在B细胞淋巴瘤、白血病等血液系统恶性肿瘤的治疗中取得了突破性成就。基于该疗法独特的治疗原理，研究人员积极探索以拓展其在其他疾病领域的应用，其中，CAR-T细胞治疗在自身免疫性疾病（autoimmune disease，AID）的治疗中展现出巨大潜力并备受关注。目前，AID的传统治疗方案（如糖皮质激素、免疫抑制剂和生物制剂等）常面临疗效有限、缓解期短及长期毒性等诸多问题。相比之下，CAR-T细胞治疗凭借其精准靶向和可诱导持续无药物缓解的优势，成为AID极具前景的治疗策略。该文回顾CAR-T细胞治疗在多种AID中的临床前和临床研究进展，阐述该疗法清除致病性B细胞及重建免疫平衡的可行性。同时重点探讨CAR-T细胞治疗面临的主要挑战，包括不良反应、持久性不足及部分患者存在抵抗性等问题，并进一步从优化嵌合抗原受体（chimeric antigen receptor，CAR）结构、探索特异性靶点及开发通用型CAR-T细胞等方面提出应对策略，阐释其未来的发展方向，旨在为CAR-T细胞治疗在AID中的进一步开发和优化提供理论依据。

关键词: 嵌合抗原受体T细胞, 细胞免疫疗法, 自身免疫性疾病

Abstract:

Chimeric antigen receptor T cell (CAR-T) therapy, which involves genetically engineering T cells to specifically recognize and efficiently eliminate target cells, has achieved groundbreaking success in treating hematological malignancies such as B-cell lymphoma and leukemia. Driven by its unique mechanism of action, research into extending its applications to other disease areas is actively underway. In particular, CAR-T therapy has shown significant potential in treating autoimmune diseases (AIDs), attracting considerable attention. Current conventional treatments for AIDs, including glucocorticoids, immunosuppressants, and biologics, are often associated with limitations such as limited efficacy, short duration of remission, and long-term toxicity. In contrast, CAR-T therapy has emerged as a highly promising treatment strategy for AIDs, owing to its advantages of precise targeting and the capacity to induce sustained, drug-free remission. This article reviews recent preclinical and clinical advances in CAR-T therapy for various AIDs, demonstrating its feasibility in eradicating pathogenic B cells and reestablishing immune tolerance. It also examines the major challenges confronting this treatment approach, including adverse effects, limited persistence, and treatment resistance in some patients. Furthermore, strategies to address these challenges are discussed, focusing on the optimization of the chimeric antigen receptor (CAR) structure, the exploration of novel specific targets, and the development of universal CAR-T products. Finally, future research directions are outlined, with the aim of providing a rational foundation for the further development and refinement of CAR-T therapy for AIDs.

Key words: chimeric antigen receptor T cell, cellular immunotherapy, autoimmune diseases

中图分类号:

R593.2

王雪懿, 李本尚. CAR-T细胞治疗自身免疫性疾病的研究述评[J]. 上海交通大学学报（医学版）, 2025, 45(11): 1432-1442.

WANG Xueyi, LI Benshang. Review of CAR-T cell therapy for autoimmune diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(11): 1432-1442.

图/表 5

参考文献 76

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Disease	Target antigen	CAR-T cell type	Experimental model	Reference
SLE	CD19	anti-CD19 CAR-T	MRL/lpr mice, (NZB×NZW) F1 mice	[15]
SLE	CD19	anti-CD19 CAR-T	MRL/lpr mice	[16]
RA	antigenic FITC peptide	anti-FITC CAR-T	CIA mice	[22]
RA	CⅡ-specific autoimmune CD4⁺ T cells	DR1-CII CAR-T	CIA mice	[23]
T1DM	I-A^g7-B:9-23(R3) antigen complex	mAb287 CAR-T	NOD mice	[27]
	Insulin or IGPR-specific CD8⁺ T cells	Insulin/IGPR-reactive CAR-T	NOD mice	[28]
	Pancreatic β cell-specific CD4⁺ T cells	^5MCAR-CTLs	NOD mice	[29]
	Insulin	Insulin-specific CAR-Treg	NOD mice	[30]
	HPi2	HPi2 CAR-Treg	Human pancreatic β cell line, mouse β cell line	[31]
PV	Dsg3-specific B cells	Dsg3 CAAR-T	NSG-PV hybridoma model	[32]
PV	Dsg3-specific B cells	Dsg3 CAAR-T	Active immune PV mice, NSG-PV hybridoma model	[33]
UC	CEA	CEA CAR-Treg	CEA-transgenic mice, AOM-DSS-CRC model	[34]
	TNP	TNP-TPCR Treg	hapten-COL model	[35]
	FliC	FliC CAR-Treg	DNBS-COL NSG model	[36]
MS	MOG	CARαMOG-FoxP3-Treg	EAE mice	[37]
	MOG and MBP	MOG/MBP CAR-Tregs	EAE mice	[38]
	CD19	anti-CD19 CAR-T	EAE mice	[39]
	CD19	anti-CD19 CAR-T	OSE mice	[40]
GVHD	HLA-A2	HLA-A2 CAR-Treg	GVHD mice	[41]
ANCA-AVV	CD19	anti-CD19 CAR-T	MPO-AVV mice	[42]
MG	anti-MuSK B cells	MuSK CAAR-T	NSG Nalm-6 xenografted mice, syngeneic MuSK EAMG mice	[43]
NMDAR encephalitis	NMDAR autoantibodies	NMDAR CAAR-T	NSG xenograft model	[44]

Disease	Target antigen	CAR-T cell type	Experimental model	Reference
SLE	CD19	anti-CD19 CAR-T	MRL/lpr mice, (NZB×NZW) F1 mice	[15]
SLE	CD19	anti-CD19 CAR-T	MRL/lpr mice	[16]
RA	antigenic FITC peptide	anti-FITC CAR-T	CIA mice	[22]
RA	CⅡ-specific autoimmune CD4⁺ T cells	DR1-CII CAR-T	CIA mice	[23]
T1DM	I-A^g7-B:9-23(R3) antigen complex	mAb287 CAR-T	NOD mice	[27]
	Insulin or IGPR-specific CD8⁺ T cells	Insulin/IGPR-reactive CAR-T	NOD mice	[28]
	Pancreatic β cell-specific CD4⁺ T cells	^5MCAR-CTLs	NOD mice	[29]
	Insulin	Insulin-specific CAR-Treg	NOD mice	[30]
	HPi2	HPi2 CAR-Treg	Human pancreatic β cell line, mouse β cell line	[31]
PV	Dsg3-specific B cells	Dsg3 CAAR-T	NSG-PV hybridoma model	[32]
PV	Dsg3-specific B cells	Dsg3 CAAR-T	Active immune PV mice, NSG-PV hybridoma model	[33]
UC	CEA	CEA CAR-Treg	CEA-transgenic mice, AOM-DSS-CRC model	[34]
	TNP	TNP-TPCR Treg	hapten-COL model	[35]
	FliC	FliC CAR-Treg	DNBS-COL NSG model	[36]
MS	MOG	CARαMOG-FoxP3-Treg	EAE mice	[37]
	MOG and MBP	MOG/MBP CAR-Tregs	EAE mice	[38]
	CD19	anti-CD19 CAR-T	EAE mice	[39]
	CD19	anti-CD19 CAR-T	OSE mice	[40]
GVHD	HLA-A2	HLA-A2 CAR-Treg	GVHD mice	[41]
ANCA-AVV	CD19	anti-CD19 CAR-T	MPO-AVV mice	[42]
MG	anti-MuSK B cells	MuSK CAAR-T	NSG Nalm-6 xenografted mice, syngeneic MuSK EAMG mice	[43]
NMDAR encephalitis	NMDAR autoantibodies	NMDAR CAAR-T	NSG xenograft model	[44]

Disease	Target antigen	CAR-T cell source	Sample size/n	Disease status	Efficacy	Reference
SLE	CD19	Autologous	1	Refractory	Drug-free remission in 44 d	[17]
	CD19	Autologous	5	Refractory	Drug-free remission within 3 months	[18]
	CD19	Allogeneic	3	Refractory	Clinical remission in 12 months	[45]
	BCMA & CD19	Autologous	1	Refractory	Drug-free remission in 23 months	[19]
	BCMA & CD19	Autologous	13	Relapsed/refractory: 2. Refractory: 11	11 cases: drug-free remission in 12‒46 months	[46]
ASS	CD19	Autologous	1	Refractory	Drug-free remission in 180 d	[24]
	CD19	Autologous	1	Refractory	Drug-free remission in 150 d	[25]
	CD19	Autologous	1	Refractory	Clinical and serological remission in 240 d	[26]
SSc	CD19	Autologous	1	Refractory	Clinical and serological remission in 6 months	[47]
	CD19	Autologous	3	Refractory	Drug-free remission in 15 months	[48]
	CD19	Autologous	1	Refractory	Clinical and serological remission in 11 months	[49]
	CD19	Allogeneic	2	Refractory	Drug-free remission in 6 months	[50]
MS	CD19	Autologous	2	Refractory	Clinical remission in 100 and 28 d	[51]
NMOSD	BCMA	Autologous	12	Relapsed/refractory	11 cases: Drug-free remission in 5.5 months	[52]
MG	BCMA	Autologous	14	Refractory	Clinical remission within 6‒12 months	[53]
MG	CD19	Autologous	2	Refractory	Clinical remission in 4 and 6 months	[54]
MMN	CD19	Autologous	1	Refractory	Clinical and serological remission in 6 months	[55]

Disease	Target antigen	CAR-T cell source	Sample size/n	Disease status	Efficacy	Reference
SLE	CD19	Autologous	1	Refractory	Drug-free remission in 44 d	[17]
	CD19	Autologous	5	Refractory	Drug-free remission within 3 months	[18]
	CD19	Allogeneic	3	Refractory	Clinical remission in 12 months	[45]
	BCMA & CD19	Autologous	1	Refractory	Drug-free remission in 23 months	[19]
	BCMA & CD19	Autologous	13	Relapsed/refractory: 2. Refractory: 11	11 cases: drug-free remission in 12‒46 months	[46]
ASS	CD19	Autologous	1	Refractory	Drug-free remission in 180 d	[24]
	CD19	Autologous	1	Refractory	Drug-free remission in 150 d	[25]
	CD19	Autologous	1	Refractory	Clinical and serological remission in 240 d	[26]
SSc	CD19	Autologous	1	Refractory	Clinical and serological remission in 6 months	[47]
	CD19	Autologous	3	Refractory	Drug-free remission in 15 months	[48]
	CD19	Autologous	1	Refractory	Clinical and serological remission in 11 months	[49]
	CD19	Allogeneic	2	Refractory	Drug-free remission in 6 months	[50]
MS	CD19	Autologous	2	Refractory	Clinical remission in 100 and 28 d	[51]
NMOSD	BCMA	Autologous	12	Relapsed/refractory	11 cases: Drug-free remission in 5.5 months	[52]
MG	BCMA	Autologous	14	Refractory	Clinical remission within 6‒12 months	[53]
MG	CD19	Autologous	2	Refractory	Clinical remission in 4 and 6 months	[54]
MMN	CD19	Autologous	1	Refractory	Clinical and serological remission in 6 months	[55]

Disease	Co-stimulatory molecule	Sample size/n	CRS			ICANS/n (%)	Hematologic toxicity/n (%)	Infection/ n (%)	Reference
Disease	Co-stimulatory molecule	Sample size/n	Incidence/n (%)	Grade	Duration/d	ICANS/n (%)	Hematologic toxicity/n (%)	Infection/ n (%)	Reference
SLE	4-1BB	1	0 (0)	—	—	0 (0)	0 (0)	UTI: 1 (100)	[17]
	4-1BB	5	3 (60)	Grade 1	Median: 2 (2‒3)	0 (0)	0 (0)	URTI: 3 (60). Otitis: 1 (20)	[18]
	CD28	3	0 (0)	—	—	0 (0)	Thrombocytopenia: 1 (33)	URTI: 1 (33)	[45]
	CD28 (anti-BCMA), 4-1BB (anti-CD19)	10	9 (90)	<grade 3	Not reported	0 (0)	Leucopenia: 5 (50). Neutropenia: 4 (40). Anemia: 5 (50). Lymphocytopenia: 4 (40)	COVID-19 infection: 8 (80). UTI: 1 (10)	[46]
ASS	4-1BB	1	1 (100)	Grade 1	3	0 (0)	0 (0)	Enteritis: 1 (100)	[24]
	4-1BB	1	1 (100)	Grade 1	Not reported	1 (100)	0 (0)	Herpes simplex: 1 (100)	[25]
	4-1BB	1	1 (100)	Grade 1	7	0 (0)	0 (0)	0 (0)	[26]
SSc	4-1BB	1	1 (100)	Grade 1	1	0 (0)	0 (0)	0 (0)	[47]
	4-1 BB	3	2 (67)	Grade 1	Median: 5 (2‒7)	0 (0)	0 (0)	Cellulitis: 1 (33). URTI: 1 (33)	[48]
	CD28 & 4-1BB	1	1 (100)	Grade 1	Not reported	0 (0)	0 (0)	0 (0)	[49]
	CD28	2	0 (0)	—	—	0 (0)	0 (0)	0 (0)	[50]
MS	CD28	2	1 (50)	Grade 1	6	0 (0)	0 (0)	0 (0)	[51]
NMOSD	4-1BB	12	12 (100)	Grade 1: 11. Grade 2: 1	Median: 3.5 (1‒8)	0 (0)	Leukopenia: 12 (100). Neutropenia: 12 (100). Anemia: 6 (50). Lymphocytopenia: 12 (100). Thrombocytopenia: 3 (25)	7 (58)	[52]
MG	Unknown	14	0 (0)	—	—	0 (0)	0 (0)	0 (0)	[53]
MG	CD28	2	2 (100)	Grade 1: 1. Grade 2: 1	Patient 1: 10. Patient 2: 9	1 (50)	0 (0)	Tooth pulpitis: 1 (50)	[54]
MMN	CD28	1	1 (100)	Grade 2	3	1 (100)	Neutropenia: 1 (100)	0 (0)	[55]