Shifting gears with CAR T cells for autoimmune diseases

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Just a few weeks ago at the American Society of Hematology Annual Meeting, Mueller et al. presented remarkable data from their ongoing study testing CD19-directed chimeric antigen receptor (CAR) T cell therapy for autoreactive B cell diseases including systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc).¹

Historically, the treatment of autoimmune disorders has focused on management without intent for cure. B cell-targeted therapies approved for SLE such as the anti-CD20 rituximab have shown variable response rates and relapse after treatment.^2,3 Rituximab depletes pre-B cells and mature B cells that express CD20 while sparing mature autoreactive plasma cells that do not express CD20. Conversely, CD19 is expressed at all stages of B cell differentiation. Preclinical murine studies of CD19-CAR therapy with primary intent of treating active SLE demonstrated effective B cell depletion, improved SLE signs, and enhanced overall survival.^4,5 CD19-CAR T cells from patients with active SLE have been successfully generated with high expansion rates and viability.⁶ In 2022, Mackensen et al. published data from 5 patients with severe refractory SLE showing that CD19-CAR therapy was highly effective and well tolerated with only mild cytokine release syndrome (CRS).⁷ Most SLE-associated antibodies were decreased post-CAR infusion, and there was only a mild to modest impact on preexisting humoral immunity.⁸

In the update presented by Mueller et al., 15 patients (8 SLE, 4 SSc, and 3 IIM) with active autoimmune disease complicated by life-threatening organ involvement and failure of multiple immunomodulatory therapies (median 5 prior lines) received a single infusion of autologous CD19-CAR T cells after fludarabine and cyclophosphamide lymphodepletion with a median post-infusion follow up of 12 months (2–28 months).¹ All 8 patients with SLE achieved and maintained complete remission after 3 months with a SLE disease activity index of 0. All 3 patients with IIM experienced major improvement and ongoing normalization of creatine kinase after 3 months. Of the 4 patients with SSc, 3 with >3 months follow up showed decreased disease activity. Of note, all 15 patients entirely stopped immunosuppressive drugs, and 5 patients with SLEs with follow up 14–24 months sustained remission despite reconstitution of B cells, as evidenced by normal complement C3, absent to minimal proteinuria, and persistent autoantibody seroconversion. CAR T therapy proved tolerable, with CRS of grade 0 in 4 patients, grade 1 in 10 patients, and grade 2 in 1 patient. Six patients received tocilizumab. One case of grade 1 immune effector cell-associated neurotoxicity syndrome that presented as vertigo was reported 2 weeks after CAR T infusion. To date, this represents the largest clinical trial of cellular therapy for autoimmune diseases.

Another study has demonstrated that CD19-CAR T cells can deplete autoreactive B cell-secreting antibodies that target platelets in immune thrombocytopenic purpura (ITP).⁹ Jie Zhou et al. constructed GPIbα chimeric autoantibody receptor (CAAR) T cells that can specifically delete autoreactive platelet-depleting B cells in ITP.¹⁰ CAAR T cells have also been developed for N-methyl D-aspartate receptor encephalitis,¹¹ multiple sclerosis,¹² and pemphigus vulgaris.¹³ Moreover, a phase 1 clinical trial is studying a desmoglein 3 CAAR T therapy in mucosal-dominant pemphigus vulgaris (ClinicalTrials.gov: NCT04422912).¹⁴ Another example is the muscle-specific tyrosine kinase-based CAAR T therapy for myasthenia gravis (ClinicalTrials.gov: NCT05451212).¹⁵

In addition, CAR-based immunotherapies for autoimmune diseases include peptide major histocompatibility complex (pMHC)-CAR T cells and CAR regulatory T cells (Tregs) for type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, and transplantation. In pMHC-CAR T cells, the targeting module of CAR is replaced by a known autoimmune peptide MHC molecule. The myelin oligodendrocyte glycoprotein peptide 35-55 MHC class II-CAR could prevent the induction of experimental autoimmune encephalomyelitis.¹⁶

As of December 2023, there are 22 clinical trials recruiting patients with autoimmune diseases for CAR therapy as reported by clinicaltrials.gov (Table 1), showing a highly encouraging first glance at how treatment may evolve for autoreactive B cell diseases. The clinical progress of CD19-CAR T cell therapy for autoimmune diseases is evolving in tandem with innovations in CAR-T cell technology utilizing alternative constructs, immune effector cells such as Tregs, as well as novel targets for autoreactive B cells.^17,18

Table 1.

Current, actively recruiting clinical trials

Intervention	Disease	Identifier	Phase
CD19-CAR T cells	SLE	NCT06056921	1
		NCT05765006	1
		NCT05869955	1
	SLE, LN	NCT06121297	1/2
	LN	NCT05938725	1
	NMOSD	NCT05828212	1
	MG	NCT05828225	1
	IIM	NCT06154252	1/2
Universal CD19-CAR T cells	SLE, SS, SSc, IIM, ANCA-associated vasculitis, anti-phospholipid syndrome	NCT05859997	N/A
CD19/BCMA-CAR T cells	SLE	NCT05858684	early 1
		NCT05846347	1
		NCT05474885	1
	LN	NCT05085418	early 1
	scleroderma	NCT05085444	early 1
	SS	NCT05085431	early 1
	POEMS syndrome, amyloidosis, AIH	NCT05263817	early 1
BCMA-CAR T cells	NMOSD, MG, chronic inflammatory demyelinating polyradiculopathy, immune-mediated necrotizing myopathy	NCT04561557	early 1
	MG	NCT04146051	2
CD19, BCMA, CD13, and BAFF-R CAR T cells	PV, SLE, AIH, SS	NCT05459870	1/2
CD7-CAR T cells	Crohn’s disease	NCT05239702	early 1
MuSK-CAAR T cells	MuSK MG	NCT05451212	1
Desmoglein-3-CAAR T cells	muscle-dominant PV	NCT04422912	1

All recruiting clinical trials utilizing CAR T or CAAR T for autoimmune disease as of December 2023 in clinicaltrials.gov. SLE, systemic lupus erythematosus; LN, lupus nephritis; MG, myasthenia gravis; SS, Sjogren’s syndrome; SSc, systemic sclerosis; ANCA, anti-neutrophilic cytoplasmic antibody; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities; AIH, autoimmune hemolytic anemia; NMOSD, neuromyelitis optica spectrum disorder; PV, pemphigus vulgaris; MuSK, muscle-specific tyrosine kinase.