Chimeric antigen receptor (CAR) therapies for precise eradication of pathogenic cells in autoimmunity

Abstract

CAR-T cells (CAR-Ts) are genetically engineered T lymphocytes to express a receptor construct bearing an extracellular recognition domain that guides the killing specificity, a transmembrane domain, and an intracellular domain that elicits effector signaling. Upon encountering the target cell, CAR-Ts accomplish their cytolytic effector function directly via engagement of pro-apoptotic pathways and exocytosis of perforin and granzymes, or indirectly via secretion of cytokines that activate NK cells. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 or BCMA, were initially approved for the treatment of late-stage hematologic malignancies. The last five years, mounting evidence from small studies in humans, employing autologous CAR-Ts targeting CD19 to selectively eliminate CD19 + cell subsets from the pool of the B-cell lineage, have revealed acceptable safety profile and encouraging efficacy in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis. Herein, we focus on a series of groundbreaking reports published within 2025 that enlighten the arising transformational potential and the emerging challenges of the CAR-based therapies regarding the management of life-threatening endotypes of autoimmune diseases.

Introduction

Chimeric antigen receptor (CAR) T cells are genetically engineered T lymphocytes to express a receptor construct comprised of an extracellular recognition domain that guides the killing specificity, a transmembrane region, and an intracellular domain that triggers effector signaling (Fig. 1A) [1]. Upon encountering the target cell, CAR-T cells (CAR-Ts) execute their cytolytic effector activity directly through engagement of pro-apoptotic pathways and exocytosis of perforin (a glycoprotein responsible for pore formation in cell membranes of target cells) and granzymes (granule-secreted serine proteases), or indirectly via secretion of cytokines that activate natural killer (NK) cells (Fig. 1B) [2]. Among the cytokines secreted by CAR-Ts, tumor necrosis factor (TNF) and interferon gamma (IFNg) have been involved in driving both the therapeutic capacity of CAR-T cells to directly kill target cells as well as aspects of the CAR-T cell-associated side effects, known as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [2, 3]. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 (the major stimulatory co-receptor of B cells) or B-cell maturation antigen (BCMA; also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17)), were initially approved for the treatment of late-stage hematologic malignancies [1, 2]. During the last five years, accumulating evidence from small studies in humans, using autologous CAR-Ts targeting CD19 and/or BCMA to selectively eliminate CD19 + and/or BCMA + cell subsets from the pool of the B-cell lineage, have demonstrated adequate safety profile and favorable efficacy in refractory to treatment systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), multiple sclerosis (MS), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), and autoimmune hemolytic anemia [4–17]. Table 1 summarizes the key studies with autologous CAR-T cells in autoimmune diseases including data on study design, CAR target, duration of follow-up, and side effects with a focus on the incidence of CRS and ICANS. In the next sections we elaborate upon a series of impactful reports appeared within 2025 that shed new light on the arising transformational potential and the growing challenges of the CAR-based therapies concerning the management of grievous endotypes of autoimmune diseases.

Fig. 1.

Structure of chimeric antigen receptors (CAR) and function of CAR-T cells. A CAR structure: CARs include an extracellular recognition domain, a transmembrane domain, and an intracellular signaling domain. In conventional CARs, the extracellular recognition domain is typically a single-chain variable fragment variable (scFv; a fusion protein of the variable regions of the heavy (VH) and the light (VL) immunoglobulins that are connected by a short flexible peptide linker). This domain defines the killing specificity of the CAR-T cell. Transmembrane domain connects the recognition domain with the intracellular signaling domain. The intracellular domain is typically a fusion construct comprising a co-stimulatory domain (e.g., CD28 (a differentiation antigen expressed on thymocytes and most mature T cells, including all CD4 T cells and CD8 T cells with cytolytic activity) or CD137 (a member of the TNF receptor family also known as 4-1BB) and a T-cell activation domain bearing immunoreceptor tyrosine-based activation motifs (ITAM; a signaling motif that is phosphorylated by Src family kinases, enabling the recruitment and activation of Syk family kinases, thereby modulating innate and adaptive immune responses). B CAR-T cell function: Engagement of the CAR by the cognate ligand induces cytolysis of the target cell via (1) potentiation of pro-apoptotic pathways, (2) exocytosis of perforin and granzymes, and (3) secretion of cytokines that activate NK cells

Table 1.

Key studies with autologous CAR-T cells in autoimmune diseases

Systemic Lupus Erythematosus (SLE)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
8	CD19	Autologous CAR-T (MB-CART19.1)	FLU + CY	6–29 mo	CRS grade 1 (n = 5) ICANS (n = 0)	[5]
7	BCMA	Autologous CAR-T (PRG1801)	FLU + CY	6–12 mo	CRS grade 1 (n = 1) ICANS (n = 0)	[6]
13	Dual: CD19 & BCMA	Autologous cCAR-T (BCMA-CD19 cCAR)	CY or FLU + CY	Up to 46 mo	CRS grade 1 (n = 9) ICANS (n = 0)	[17]
15	Dual: CD19 & BCMA	Autologous CAR-T	FLU + CY	613–1134 days	CRS grade 1 (n = 13) ICANS (n = 0)	[7]

Systemic Sclerosis (SSc)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
4	CD19	Autologous CAR-T (MB-CART19.1)	FLU+CY	4–13 mo	CRS grade 1 (n=3) ICANS (n=0)	[5]
6	CD19	Autologous CAR-T (MB-CART19.1)	FLU+CY	342–585 days	CRS grade 1 (n=3) CSR grade 2 (n=2) ICANS (n=0)	[8]

Idiopathic Inflammatory Myositis (IIM)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
3	CD19	Autologous CAR-T (MB-CART19.1)	FLU+CY	5–18 mo	CRS grade 1 (n=2) CRS grade 2 (n=1) ICANS grade 1(n=1)	[5]

Multiple Sclerosis (MS)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
2	CD19	Autologous CAR-T (KYV-101)	FLU+CY	28–100 days	CRS grade 1 ICANS	[10]
5	BCMA	Autologous CAR-T	N/A	Up to 9 mo	CRS grade 1 (n=4) ICANS	[11]

Myasthenia Gravis (MG)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
1	CD19	Autologous CAR-T	FLU+CY	60 days	CRS (n=0) ICANS (n=0)	[12]
14	BCMA	Autologous rCAR-T (Descartes-08)	No	Up to 12 mo	CRS (n=0) ICANS (n=0)	[13]
18	Dual: CD19 & BCMA	Autologous CAR-T	FLU+CY	Up to 36 mo	CRS grade 1 (n=7) ICANS (n=0)	[14]

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
2	BCMA	Autologous CAR-T (CT103A)	FLU+CY	12–24 mo	CRS grade 1 (n=2) ICANS (n=0)	[15]

n Number of enrolled patients, CAR Chimeric antigen receptor, cCAR compound CAR, rCAR RNA engineered CAR, LDT Lymphodepletion therapy, FLU Fludarabine, CY Cyclophosphamide, BCMA B-cell maturation antigen, CRS Cytokine release syndrome, ICANS Immune effector cell-associated neurotoxicity syndrome, N/A Not available

Opportunity for precise depletion of disease-relevant cells

In humans, the B-cell compartment is highly heterogeneous and it is shaped over the years through defined developmental stages and activation pathways, which take place primarily within the bone marrow, the peripheral lymph nodes, and the bloodstream [18]. The various B-cellsubpopulations may contribute to autoimmune diseases pathogenesis via a disease-specific combination of mechanisms including antibody production, proinflammatory cytokine secretion, and antigen presentation to T cells [18]. In this sense, different autoimmune disease settings may require eradication of different B-cell subpopulations. Differential expression of the cell-surface proteins CD20, CD19, and BCMA enable the identification and targeting of B-cell subsets with distinct and overlapping effector functions [19]. CD20 is expressed during B-cell development and maturation from pre-B cell stage through immature, naïve, and memory cells, but its expression is gradually downregulated or even lost during terminal differentiation into plasmablasts and plasma cells. CD19 is broadly expressed across development from pro-B cells to late plasmablasts (activated B cells that secrete antibodies) [18, 19]. In this context, CAR-T-mediated depletion of CD19 + B cells divulged sustained efficacy in life-threatening and/or conventinal treatment-resistant cases of SLE, SSc, IIM, MS, and MG (Table 1) [4, 5, 8, 10, 12]. BCMA is primarily expressed on antibody-secreting cells (ASCs) including plasmablasts, short- and long-lived plasma cells [18, 19]. Two recently published studies have shown for the first time that the eradication of BCMA + ASCs by administration of BCMA-only targeting CAR-Ts led to reduction of global immunoglobulin and auto-antibody titers and sustained clinical improvement in 7 subjects with active lupus nephritis (LN) and 1 patient with IIM [6, 9]. Additional case reports and small series of patients have shown positive efficacy of BCMA-targeting CAR-T therapies in MS, MG, and CIDP (Table 1) [11, 13, 15].

Further studies are necessary to identify and characterize the disease-relevant B-cell subpopulations and inform precise selection of CAR-T specificity for the various clinical endotypes of the broad spectrum of autoimmune diseases. Antibody-mediated diseases is a subgroup of autoimmune diseases, where specific auto-antibodies against known auto-antigens directly drive disease manifestations. Chimeric auto-antibody receptor (CAAR) technology is a modification of the conventional CAR technology, enabling the genetic engineering of T cells to express a selected auto-antigen at the extracellular recognition domain that guides the killing specificity [2, 20]. Thus, CAAR-T cells target for depletion only the B cells expressing B-cell receptors (BCRs) with specificity for the auto-antigen expressed on the recognition domain of the CAAR [19]. Myasthenia gravis (MG) and pemphigus vulgaris (PV) are prototypical antibody-mediated diseases driven by auto-antibodies against muscle-specific tyrosine kinase (MuSK; a receptor tyrosine kinase that is essential for the formation and stabilization of neuromuscular junctions) and acetylcholine receptor (AChR) for MG and desmoglein 3 (Dsg3; a cadherin-type cell adhesion molecule integral to forming and maintaining desmosomes in epithelial tissues) for PV [2]. MuSK-, AChR-, and Dsg3-CAAR-T cells are in different preliminary stages of clinical development (e.g., clinical trials.gov ID: NCT05451212 for MuSK-CAAR-T cells and NCT04422912 for Dsg3-CAAR-T cells) aiming to provide proof-of-concept. Further clinical trials are required to test whether CAAR-T-based approaches can achieve precise depletion of the autoreactive B-cells clones and of the pathogenic auto-antibodies only, without a broader impact on the B-cell subsets required for defense and on the global immunoglobulin titers [2, 21].

Opportunity for “deeper” immune reset through lymphatic tissue B-cell depletion

Following the marketing authorization of rituximab (RXT) for the treatment of rheumatoid arthritis (RA), multiple next-generation B cell-depleting modalities have been designed, including monoclonal antibodies (Mabs) against CD19, glycol-engineered Mabs against CD20 (a common B-cell marker also called L26, membrane spanning 4 domains (MS4A1)), and bispecific T-cell engagers (e.g., antibodies or engineered proteins that engage concomitantly the BCMA on B cells and the CD3 (a protein complex and T-cell co-receptor) on T cells) [18]. Although circulating B cells are effectively depleted by these molecules, a common theme for all the protein-based modalities is the suboptimal depletion of the of B-cell compartment from bone marrow, peripheral lymph nodes, and other tissues (e.g., synovium) [22]. Proteins rely for tissue penetrance on passive diffusion and the large size of these protein constructs may be a limiting factor. The therapeutic impact of B-cell depletion is explained by the concept of immune reset [2]. Pharmacologic depletion of disease-driving B-cell subsets is followed by a reconstitution phase, where the B-cell compartment is repopulated by bone marrow-derived naïve progenitors going through developmental checkpoints, with the expectation for an immune reset by shaping a new B-cell repertoire with lower autoreactivity and disease-driving potential. In this context, the effectiveness and safety of B cell-targeting modalities depends on the breadth and depth of immune reset [1, 2, 22].

The hypothesis behind the use of CAR-Ts for B-cell depletion in autoimmune diseases is that they display improved tissue penetrance enabling deeper depletion of the disease-driving cell subpopulations, resulting in more effective immune reset. A recently published study by Tur et al. evaluated for the first time in humans this hypothesis by performing sequential lymph node biopsies in patients with various autoimmune diseases, to measure the comparative depth of tissue depletion of B-cell compartment across protein- and cell-based B cell-depleting modalities [22]. Their findings suggest that although next-generation protein-based B-cell depletion molecules (e.g., a glycol-engineered anti-CD20 and a CD19/CD3 T-cell engager) improved the depth of B-cell depletion in lymphoid organs as compared to RXT, CD19-CAR-T cell therapies displayed superiority with consistent full lymph node depletion along with disruption of follicular lymph node architecture. Finally, Garantziotis et al. assessed the molecular signatures of the immune reset induced by anti-CD19 CAR-Ts in SLE patients [23]. They demonstrated that anti-CD19 CAR-Ts therapies induce a stronger downregulation of interferon and DNA repair pathways compared to conventional protein-based B-cell targeting therapies, potentially providing a molecular description of the immune reset achieved by the deeper B-cell depletion.

Technological advances to mitigate challenges of CAR-T therapies

The requirement of autologous cells, due to the risks of rejection and graft vs. host disease (GVHD), hampers the broader application of conventional CAR-T therapies [2]. At the same time, harvesting high-quality cells for proper genetic engineering from patients with severe autoimmune diseases, especially if they are under cytotoxic medications, is not always feasible. Gene editing of cells derived from healthy donors has allowed the knock-out of T-cell receptor alpha constant (TRAC; encoding the constant domain of the T-cell receptor (TCR) alpha chain), human leukocyte antigen (HLA)-A, HLA-B, and class II major histocompatibility complex (MHC) transactivator (CIITA; a master controller of adaptive immunity), enabling the generation of high-quality hypoimmune cells with minimal risk for triggering GVHD or rejection if infused in another donor [24, 25]. Administration of allogeneic hypoimmune CD19-targeting CAR-Ts induced deep B-cell depletion and disease control, with no evidence of GVHD, in patients with treatment-refractory SLE, SSc, and IIM (Table 2) [24–27]. Another allogeneic product was manufactured by transducing NK cells derived from healthy donors’ cord blood or peripheral blood with CAR-bearing vectors to generate CD19-targeting CAR-NK cells [28]. Infusion of CD19 CAR-NK cells in 18 patients with relapsed or refractory SLE was well tolerated (Table 2). Among the 9 patients with the longest follow-up (>12 months), 6 achived Definition of Remission in SLE (DORIS) remission and lupus low-disease activity [28]. Inducible pluripotent stem cell (iPSC)-derived CAR natural-killer (CAR-NK) cells with CD19/BCMA dual targeting, were recently developed with genetic editing to reduce alloreactivity and improve in vivo performance [29]. Administration of the allogeneic iPSC-derived CD19/BCMA CAR-NK in a patient with severe SSc was also well tolerated (Table 2) and led to B-cell depletion, reduction of auto-antibody titers, and clinical improvement [29].

Table 2.

Key studies with allogeneic CAR-based approaches in autoimmune diseases

Systemic Lupus Erythematosus (SLE)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
5	CD19	Allogeneic CAR-T (YTS109)	FLU + CY	3–6 mo	CRS grade 1 (n = 2) ICANS (n = 0)	[24]
4	CD19	Allogeneic CAR-T (TyU19)	FLU + CY	3–6 mo	CRS grade 1 (n = 4) ICANS (n = 0)	[26]
3	CD19	Allogeneic CAR-T (TyU19)	FLU + CY	12 mo	CRS (n = 0) ICANS (n = 0)	[27]
18	CD19	Allogeneic cord blood- or peripheral blood-derived CAR-NK	FLU + CY	5–18 mo	CRS grade 1 (n = 1) ICANS (n = 0)	[28]

Systemic Sclerosis (SSc)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
2	CD19	Allogeneic CAR-T (TyU19)	FLU+CY	6 mo	CRS (n=0) ICANS (n=0)	[25]
1	Dual: CD19 & BCMA	Allogeneic  iPSC-derived CAR-NK (QN-139b)	FLU+CY	6 mo	CRS (n=0) ICANS (n=0)	[29]

Idiopathic Inflammatory Myositis (IIM)
n	Target	Product Type	LDT	Follow up	CRS/ICANS (n)	Ref
1*	CD19	Allogeneic CAR-T (TyU19)	FLU+CY	6mo	CRS (n=0) ICANS (n=0)	[25]

n Number of enrolled patients, CAR Chimeric antigen receptor, LDT Lymphodepletion therapy, CRS Cytokine release syndrome, ICANS Immune effector cell-associated neurotoxicity syndrome, FLU Fludarabine, CY Cyclophosphamide, BCMA B-cell maturation antigen

^*the patient was diagnosed with a subtype of IIM known as immune-mediated necrotizing myopathy (IMNM)

Genetic editing technologies aiming to improve immune compatibility of allogeneic CAR-bearing cells may pave the way for development of off-the-shelf CAR-based therapies. In the coming years, the promises for broader use with lower cost will be pressure-tested. Clinical validation of these allogeneic technologies lags autologous approaches by many years of investigation and the early studies [24–29] report limited clinical information, particularly with respect to total number of treated patients and duration of response. Table 2 summarizes the small-size studies published so far with allogeneic CAR-based approaches in autoimmune diseases.

Lymphodepletion chemotherapy is a necessary preconditioning step for conventional CAR-T therapies in order to establish a permissive in vivo environment for optimal engraftment and expansion of the engineered CAR-Ts [20]. Toxicities related to lymphodepletion chemotherapy and potential genotoxic effects of integrating viral vectors used for genetic engineering of the cells may restrict the broader use of CAR-Ts in the context of autoimmune diseases [20]. Newly emerging RNA-based approaches, not relying on viral vectors, enable the transient expression of the desired CAR by ex vivo introduction to the cells of an engineered mRNA encoding CAR (mRNA CAR-Ts) [1]. Autologous CD8 + mRNA CAR-Ts expressing a CAR-targeting BCMA have been administered in a multiple dose protocol in patients with MG, without the requirement of lymphodepletion chemotherapy [1]. Notably, the use of targeted lipid nanoparticles (tLNP) for mRNA delivery was recently shown to allow in vivo engineering and generation of CAR-Ts [30]. These mRNA-based technologies skip lymphodepletion chemotherapy and minimize the risk for genotoxicity, opening new avenues for developing safer and easier to manufacture CAR-T modalities for patients with autoimmune diseases [1]. At the same time, it should be noted that administration of tLNP or lentiviral particles can be immunogenic, and therefore in vivo engineering of CAR-Ts with repeat particle dosing may not be feasible.

Conventional CAR-T cells mediate therapeutic effects in the context of autoimmunity by killing effector subsets of B-cells. An alternative approach has recently emerged aiming to suppress, instead of killing, pathogenic cell populations. The latter has been feasible by engineering Treg cells to either express a CAR or an artificial immune receptor (AIR) [19]. Both CAR-Tregs and AIR-Tregs become activated upon the engagement of their respective receptor and suppress immune responses by producing anti-inflammatory mediators. Along these lines, it was recently shown that a single dose of CD19-targeting CAR-Tregs restricted autoantibody generation, delayed lymphopenia, and restored lymphoid organ homeostasis in a humanized murin model of SLE [31]. These preclinical data are very preliminary, but there are three ongoing clinical trials (NCT05993611, NCT05234190, and NCT04817774) purposed to evaluate safety and efficacy of CAR-Tregs in preventing GVHD and transplant rejection [32].

Safety considerations for CAR-based approaches in autoimmunity

So far, the cumulative experience from the small series and case reports of patients with different autoimmune diseases suggests that CAR-based approaches display acceptable short- and long-term safety [33]. CRS and neurotoxicity (including ICANS), may occure within 30 days post-infusion of CAR-cells. In patients with autoimmune diseases, CRS was reported with variable frequencies, but ICANS was rare (Tables 1 and 2). In the context of autoimmunity, the cases of CRS and ICANS were primarily mild (grade 1) and only few patients were treated with interleukin 6 (IL-6) inhibitors and/or steroids for symptom control [33]. In contrast to what is observed in cancer patients, there are no fatal or high-grade events of CRS and ICANS requiring intensive care unit admission. A recently published observational study including 39 patients with autoimmune diseases treated with CD19-targeting CAR-Ts has identified a new form of toxicity termed local immune effector cell-associated toxicity syndrome (LICATS), affecting 77% of patients with median time of onset 10 days from CAR-T infusion and median duration of 11 days [34]. This local inflammation, which is self-limited and organ-specific, is distinct from the systemic CRS. In LICATS there is a tropism for local inflammation in organs previously affected by the respective autoimmune disease. Skin and kidneys were preferentially involved in SLE, while muscle inflammation and dyspnoea was observed in IIM with interstitial lung disease. Mechnisticaly, LICATS is proposed to be triggered by the tissue homing of CAR-T cells, the rapid local killing of targeted B-cells, and the cleansing of cellular debries by phagocytes [34].

Other CAR therapy related AEs include prolonged cytopenias, infections, and hypogammaglobulinemia, which in some cases may require antimicrobial prophylaxis and immunoglobulin replacement therapy (IVIG) [33]. Cytoreductive toxicities due to lymphdepletion chemotherapy with fludarabine and cyclophosphamide are also observed. Additional safety considerations requiring the development of specific guidelines include vaccination windows, levels of memory and responsiveness to vaccines post-therapy, concerns regarding pregnancies, as well as offering options for fertility presertvation.

Due to the development of second primary malignancies, including CAR + lymphomas, in patients who received CAR-Ts for the management of a first hematologic cancer, the USA Food and Drug Administration (FDA) has added a boxed warning applicable to all approved CD19- and BCMA-targeting autologous CAR-T cell immunotherapies [35–41]. In some cases, molecular profiling of the second primary malignancy has revealed integration of the viral vector for the CAR construct into loci potentially implicated in oncogenesis, such as the putative tumor suppressor genes TP53 and T-cell intracellular antigen 1 (TIA1) [36, 37]. These observations support a model where the viral vector used for the engineering of CAR-T cells may induce direct gentoxicity via insertional mutagenesis. At the same time, there were other second primary malignancies with evidence of oncogenic mutations pre-exisiting the infusion of CAR-Ts and no evidence of CAR viral vector integration [38]. In anticipation of further studies and larger data-sets to resolve the debate about the actual oncogenic potential of the CAR viral vectors, a life-long monitoring for new malignancies is recommended for any patient receiving CAR-T cell therapies.

Conclusions

According to a recent review article, more than 70 clinical trials of CAR-based approaches are registered worldwide as ongoing, across a broad range of immune-mediated diseases including additional indications such as anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, antiphospholipid syndrome, Sjogren’s syndrome, IgG4-related diseases, autoimmune hemolytic anemia, and immune thrombocytopenia [32]. The recently emerged CAAR-based technologies permit precise depletion of the disease-driving autoreactive B-cells clones and provide therapeutic opportunities for antibody-mediated diseases [2, 19–21]. In addition, advanced mRNA-based technologies may lead to simpler protocols of treatment administration with improved safety profile [30].

Preliminary data from a small study suggest that B-cell-targeting CAR-Ts may have the potential to achieve a deeper immune reset in patients with autoimmune diseases, compared to protein-based therapies, due to superior tissue penetrance and more complete depletion of tissue-resident pathogenic B cells [22]. Prospective studies comparing head-to-head CAR-Ts with protein-based therapies regarding the achieved depth and breadth of B-cell depletion are required to confirm if there is any superiority of one treatment modality over the other.

Currently, there are no specific biomarkers to guide a rational selection of patients with autoimmune diseases that should be eligible for CAR-Ts. Most of the published studies have enrolled disease endotypes refractory to standard-of-care immunosuppression, with high ASC signatures. Additional research is required to identify the profile of patients that should be treated with CAR-based therapies and to define the specificity of CAR for each disease endotype.

Finally, although in hematology CAR-T cell therapies represent an approved treatment path for specific late-stage malignancies, the widespread adoption of CAR-based approaches in autoimmune disease indications faces several barriers [42]. CAR-T cell therapies are expensive with an estimated per patient cost around $500,000, imposing challenges to health-care systems regarding cost-effectiveness and reimbursement [42]. There is also the barrier of limited accessibility since autologous therapies are only feasible at specific medical centers with relevant infrastructure and expertise. Gene-editing technologies enable the development of allogeneic CAR-bearing cells, potentially empowering a broader and less costly use of off-the-shelf CAR-based therapies in patients with autoimmune diseases [24–29].

Authors’ contributions

GDK, EKB, and AGP were involved in preparation of the manuscript, critical review, and approved the final version.

Funding

This study received no external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed to the publication of this manuscript.

Competing interests

The authors declare no competing interests.