Review of CAR-T cell therapy for autoimmune diseases

doi:10.3969/j.issn.1674-8115.2025.11.003

Abstract

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

CLC Number:

R593.2

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.

Figures/Tables 5

TrendMD

References 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]