Structurally, bispecific T-cell engagers (BiTEs) consist of two single-chain variable fragments (scFvs). One of the scFvs specifically binds to the CD3 molecule on the T-cell surface—a key signaling molecule for T-cell activation—while the other scFv specifically targets a distinct antigen on the surface of target cells, such as tumor-associated antigens or pathogenic antigens in autoimmune diseases. Through this bispecific binding, BiTEs act as a “bridge” to tightly connect T cells and target cells, narrowing the distance between them and creating conditions for subsequent immune-mediated cytotoxic responses (12–14). Upon simultaneous binding of BiTE molecules to T cells and target cells, a cascade of immune responses is triggered. Activation of the CD3 molecule on the T-cell surface represents a critical step in T-cell activation. Activated T cells then release a variety of cytotoxic substances, such as perforin and granzyme. Perforin is capable of forming pores in the target cell membrane, enabling substances like granzyme to enter the interior of target cells. Once inside, granzyme activates a series of apoptotic signaling pathways, ultimately inducing target cell apoptosis and subsequent clearance (15). This mechanism of action enables BiTEs to precisely direct T cells to eliminate target cells, independent of antigen-presenting cells (APCs) and the antigen-presenting function of major histocompatibility complexes (MHCs). However, BiTEs have limitations, including a short half-life that necessitates multiple infusions. In contrast, the manufacturing process of BiTEs is relatively straightforward, with high operability and lower costs compared to CAR-T cell therapy. The production workflow involves first generating two distinct monoclonal antibodies separately. Subsequently, appropriate amounts of these two antibodies are mixed with a cross-linking agent under specific conditions to induce cross-linking between antibody molecules. Following the completion of the cross-linking reaction, purification is performed to obtain the bispecific antibody product (Figure 1). Currently, this therapeutic modality is also being explored for the treatment of rheumatic autoimmune diseases (16, 17).

Chimeric antigen receptor T-cell (CAR-T) therapy is an emerging adoptive T-cell therapy. The manufacturing process of ex vivo CAR-T cells involves multiple critical steps. First, T cells are collected from the patient’s body. As a crucial component of the immune system, T cells possess the ability to recognize and attack pathogens and abnormal cells. Through isolation techniques, T cells are separated from the patient’s blood and transported to specialized laboratories, where they undergo genetic engineering modification (Figure 1). The objective of this modification is to introduce the chimeric antigen receptor (CAR) gene into T cells (18–20). Functioning like a “navigation system” installed in T cells, CAR enables specific recognition and binding to distinct antigens on the surface of tumor cells or pathogenic cells, thereby endowing T cells with the capacity for precise targeting and attack. Unlike BiTEs, CAR-T cells can persist and proliferate long-term in vivo. Starting from the second-generation CAR-T cells, these cells have been engineered to exhibit an effector memory phenotype and possess sustained activation properties. However, the manufacturing process of CAR-T cells is relatively complex. Autologous CAR-T cells require personalized customization, which results in prolonged production time and high costs—barriers that deter many patients from accessing this therapy (21). To address the limitations of ex vivo CAR-T therapy, in vivo CAR-T therapy has been developed as a promising alternative. Its core advantage lies in the ability to achieve direct delivery and expression of CAR genes within the patient’s body, eliminating the need for ex vivo isolation, genetic modification, and expansion of autologous T cells. CAR gene delivery is primarily mediated by two categories of vectors: viral vectors (e.g., adeno-associated virus [AAV], lentivirus [LV]) and non-viral vectors (e.g., lipid nanoparticles [LNPs], targeted nanocarriers). The injected CAR gene-vector complexes recognize and bind to specific surface receptors on T cells (e.g., CD3, CD4) via vector-conjugated targeting moieties. Subsequently, the CAR genes are internalized into T cells through vector-specific delivery mechanisms, such as endocytosis for AAV and membrane fusion for LNPs. Once inside T cells, CAR genes undergo transcription and translation, and the synthesized CAR molecules are anchored to the T cell membrane via their transmembrane domains. This in situ T cell reprogramming equips naive T cells with the capacity to specifically recognize and target SLE-associated pathogenic cells. Despite these advances, in vivo CAR-T therapy still faces critical challenges, including suboptimal vector delivery efficiency, insufficient targeting specificity, short persistence, and unresolved long-term safety concerns, all of which necessitate further optimization for clinical translation (22).

Chimeric antigen receptor T-cell (CAR-T cell) therapy has shown promising prospects in the field of oncology. Based on its therapeutic mechanism, this therapy has also begun to be explored for application in autoimmune diseases. Next, we will discuss the clinical progress of CAR-T cell therapy in the treatment of rheumatic autoimmune diseases. To date, rheumatic autoimmune diseases for which CAR-T cell clinical trials have been initiated include systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, inflammatory myopathies, and rheumatoid arthritis (23) (Table 1), with variations in the selection of therapeutic targets (Figure 2).

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving multiple organs and systems (24, 25). While disease activity can be effectively controlled with standardized treatment in most patients, a subset experiences disease relapse or vital organ involvement, leading to severe complications that impair quality of life and reduce survival. Thus, there is an urgent need for novel therapeutic strategies. B cells play a critical role in SLE pathogenesis, and most emerging therapies target B cell depletion for therapeutic efficacy (26). CD19 is widely expressed on B lymphocytes, and CD19-targeted CAR-T cells can specifically eliminate B cells. Significant progress has been made in the application of CAR-T therapy for SLE, with CD19 as the most commonly used target. In August 2021, the Georgschett team reported the first case of SLE treated with CAR-T therapy (27). Subsequent studies enrolled additional SLE patients, and long-term follow-up showed that 100% of patients achieved complete short-term symptom remission and complete glucocorticoid independence. To date, 66 cases of SLE treated with CAR-T therapy have been reported, including 9 from Germany (28), 48 from China (29–34), and 9 from the United States (35, 36). Favorable efficacy and safety profiles were observed, with no high-grade adverse events reported.

Sjögren’s syndrome (SS) is a common autoimmune disease primarily affecting exocrine glands (especially salivary and lacrimal glands), leading to xerostomia and xerophthalmia (37). In SS, excessive B cell activation results in the production of autoantibodies (e.g., anti-SS-A and anti-SS-B antibodies), triggering chronic inflammation of exocrine glands (38). B cell-targeted CAR-T therapy induces profound B cell depletion and immune reconstitution in autoimmune disease patients, thereby exerting therapeutic effects. To date, only 2 clinical reports on CAR-T therapy for SS have been published. Both patients achieved drug-free remission following CD19-targeted CAR-T therapy (maximum follow-up of 18 months), with only mild cytokine release syndrome (CRS) and neurotoxicity observed. Long-term efficacy requires validation in larger cohorts (39, 40).

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and multiple organ systems (41). Its etiology remains unclear, but accumulating evidence supports a critical role of B cells in the pathophysiology of severe SSc (42, 43). Most patients have detectable autoantibodies (e.g., antinuclear antibodies [ANA], anti-Scl-70 antibodies, and anticentromere antibodies [ACA]), which are valuable for diagnosis and disease activity assessment. To date, 15 cases of SSc treated with CAR-T therapy have been reported (28, 44–48). All enrolled patients had extrapulmonary organ involvement. Following infusion of CD19-targeted CAR-T cells, all patients achieved disease remission with favorable safety profiles: no grade ≥3 CRS or neurotoxicity was observed, nor was long-term B cell aplasia detected. Some patients developed infections and hypogammaglobulinemia. Longer-term remission outcomes require continuous follow-up.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases characterized by skeletal muscle inflammation. Based on autoantibody profiles, IIMs are classified into subgroups including dermatomyositis (amyopathic subtype), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis, and overlap myositis (49, 50). B cells play a pivotal role in IIM pathogenesis (51, 52). Histopathological studies have identified B cells and plasmablasts adjacent to T cells in inflamed skeletal muscles. Additionally, rituximab-induced B cell depletion has shown efficacy in some patients with antisynthetase syndrome, further supporting the pathogenic role of B cells (53). Despite current treatments (e.g., glucocorticoids, intravenous immunoglobulin [IVIG], and B cell-targeted agents), antisynthetase syndrome is often refractory, leading to increased mortality (54). To date, 12 IIM patients (presenting with severe myositis or concurrent interstitial pneumonia) have received CAR-T therapy (28, 40, 45, 55–61). All patients exhibited favorable therapeutic responses, with improved symptoms, imaging findings, and laboratory parameters, reduced autoantibody titers, and some achieving first-time autoantibody seronegativity. The therapy had an acceptable safety profile, with no grade ≥3 CRS or high-grade neurotoxicity observed.

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease primarily affecting joint synovium, causing pain, swelling, stiffness, and in severe cases, joint deformity and dysfunction (62, 63). Although its pathogenesis is incompletely understood, protein citrullination is a well-recognized trigger of immune responses in RA (64). Serum anti-citrullinated protein antibodies (ACPAs) are specific markers for RA and correlate with disease development and progression (65–67). Thus, B cell depletion to reduce antibody production may be a viable therapeutic strategy (68, 69). Currently, only 4 cases of RA treated with CAR-T therapy have been reported (70, 71), with disease control achieved in all patients. However, only 1 patient achieved 6-month drug-free remission, while the others required maintenance therapy. Therefore, the patient selection criteria and optimal timing for CAR-T therapy in RA remain to be further explored.

Explorations into the use of chimeric antigen receptor T (CAR-T) cells in patients with autoimmune diseases have demonstrated considerable potential; however, they have also revealed several potential risks and limitations, including viral vector integration, prolonged production time, and high costs. Given these factors, alternative approaches for B-cell depletion in the treatment of systemic autoimmune diseases have garnered research interest.

Blinatumomab, the first developed bispecific T-cell engager (BiTE), targets CD19 on B cells and exhibits efficacy even at extremely low concentrations. It enables a single T cell to engage with and sequentially eliminate multiple B cells (72, 73). This agent has demonstrated favorable efficacy in the treatment of acute lymphoblastic leukemia (ALL). Recently, Georg Schett and colleagues conducted the first attempt to administer blinatumomab to patients with multidrug-resistant, refractory rheumatoid arthritis (RA). A total of 6 patients were enrolled in this study (16). All patients had previously received multiple therapies, including conventional disease-modifying antirheumatic drugs (DMARDs) and biologics, yet their disease remained poorly controlled. Following blinatumomab infusion, all patients achieved disease improvement, with no significant adverse events observed during treatment. Neither cytokine release syndrome (CRS) nor neurotoxicity was detected; only three patients developed infections, and one patient experienced mild fever (≤38°C), all of which resolved after symptomatic treatment. During subsequent short-term follow-up, these patients initiated abatacept as adjuvant therapy starting from the 4th month post-treatment, while one patient experienced disease progression prior to abatacept administration. This progression may be associated with dosage, as the dose used in this study was significantly lower than that for hematological malignancy treatment. Subsequently, the same research team enrolled an additional 4 patients (74), diagnosed with RA, Sjögren’s syndrome (SS), idiopathic inflammatory myopathy (IIM), and SS, respectively. All patients had received conventional medications and more than 5 types of biologics previously, but their disease remained active. In this cohort, teclistamab—a bispecific T-cell engager targeting BCMA×CD3—was administered. After treatment, all patients achieved disease control. Following teclistamab infusion, all 4 patients discontinued immunosuppressants; only the RA patient continued glucocorticoid therapy for efficacy maintenance, with a gradual reduction in dosage. Favorable safety profiles were observed in all patients: no neurotoxicity or CRS was detected, and the only adverse events were herpes labialis and upper respiratory tract infections. B cells were rapidly depleted in the short term, and their reappearance was detected at week 12. The newly emerging B cells exhibited phenotypic switching, presenting as naive B cells, with no subsequent disease relapse observed.

Additionally, blinatumomab has been reported for the first time in the treatment of systemic sclerosis (SSc) (75). The patient experienced rapid disease progression within 1 year of diagnosis and had a strong desire to conceive, which restricted the use of many medications. Consequently, the CD19×CD3 bispecific antibody blinatumomab was considered and administered. Following treatment, the patient’s symptoms improved rapidly, with no cytokine release syndrome (CRS), neurotoxicity, infections, or other severe toxic effects observed. During the treatment period, monitoring revealed a significant decrease in B-cell count, which provides further evidence for B-cell depletion therapy in the management of SSc.

Teclistamab is a bispecific T-cell engager (BiTE) targeting B-cell maturation antigen (BCMA) (76). Recently, the first case of a systemic lupus erythematosus (SLE) patient treated with this agent was reported in Germany. The 23-year-old patient had previously received multiple conventional medications and biologics, yet their disease remained active. Following treatment, the patient achieved rapid disease remission: the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score decreased from 20 to 0 at 6 weeks post-treatment, and autoantibody levels also declined rapidly. The treatment was well-tolerated; adverse events included grade 2 cytokine release syndrome (CRS), pneumonia, sinusitis, and hypogammaglobulinemia. No high-grade CRS or neurotoxicity was observed (Table 2).

Chimeric antigen receptor T (CAR-T) cell therapy and bispecific T-cell engagers (BiTEs) differ in multiple aspects (Table 3), and we will focus on elaborating from the following perspectives:

In the application of chimeric antigen receptor T (CAR-T) cell therapy and bispecific T-cell engager (BiTE) therapy, disease activity serves as a key indicator for determining treatment timing and regimens. Clinical studies have shown that CAR-T cell therapy can still induce an objective response rate (ORR) of 60–80% in relapsed/refractory hematological malignancy cases. However, in patients with low tumor burden, it may excessively activate the immune system, leading to a high risk of severe cytokine release syndrome (CRS). Therefore, the NCCN Guidelines recommend CAR-T therapy for patients who have failed ≥3 lines of treatment and have measurable lesions. In contrast, BiTE therapy—characterized by a short half-life and high controllability—is more suitable for maintenance treatment in patients with moderate-to-low disease activity. Thus, based on its data in oncology and the current clinical data of CAR-T therapy in rheumatic autoimmune diseases, CAR-T therapy may be more preferentially used in patients with ultra-refractory rheumatic autoimmune diseases, as well as those with rapidly progressive disease that endangers organ function.

Chimeric antigen receptor T (CAR-T) cell therapy is characterized by its core advantages of “profound elimination of pathogenic cells and achievement of relatively long-term remission,” while bispecific T-cell engagers (BiTEs) are distinguished by their features of “rapid onset of action and high safety.” For patients with rapidly progressive, refractory severe disease: BiTEs can be used first to rapidly control disease progression. If the disease stabilizes subsequently and the patient still responds to conventional medications or biologics, these conventional agents can be used for maintenance treatment; if there is no response, CAR-T cell therapy can be administered to achieve long-term remission.