A Bite of B Cells: The Potential Role of Bispecific T Cell Engager Therapy (BiTE) in Autoimmune Diseases

Presently, systemic autoimmune rheumatic diseases are deemed to be incurable chronic conditions. In the current era of biologics and small molecule inhibitors between 5% and 20% of rheumatoid arthritis (RA) diagnoses are categorized as “difficult-to-treat RA” [1]. Despite the long-term survival rate of patients with systemic lupus erythematosus (SLE) improving in recent decades, for those with late-onset SLE, infections remain the primary cause of reduced long-term survival. Additionally, the presence of multiple comorbidities significantly limits the choice of medication, thus underscoring an urgent need for innovative therapeutic approaches [2].

Chimeric antigen receptor (CAR) T cell therapy may represent a revolutionary breakthrough in the treatment of autoimmune rheumatic diseases, which involves using retroviruses to insert genetically engineered genes into T cells, transforming them to express receptors that bind to specific cells and target them for destruction. The most notable success of CAR T cell therapy has been observed in lymphoma treatment, where CD19-targeted CAR T cells achieved complete remission in 40%–54% of cases involving relapsed or refractory aggressive B-cell lymphomas [3]. A research team from the University of Erlangen-Nuremberg in Germany was the first to explore the potential application of CAR T cell therapy to systemic autoimmune rheumatic diseases, such as SLE, with the hope of even achieving a cure in cases where traditional treatments have failed. According to a case series published by Fabian Müller and colleagues, CD19-targeted CAR T cell therapy has the potential to maintain disease remission in SLE for more than 2 years [4]. Successful cases have also been reported in idiopathic inflammatory myopathies (IIMs) and systemic sclerosis (SSc), as well as pediatric SLE [5, 6]. Recently, Wang et al. [7] applied allogeneic CAR T cells for the treatment of three patients with severe autoimmune diseases and published the initial positive outcomes. The success of allogeneic CAR T cells may significantly reduce the cost and time required for CAR T cell therapy.

Before undergoing CAR T cell therapy, patients must receive chemotherapy to eliminate existing T cells in the body to prevent them from attacking the CAR T cells, which can affect the therapy's effectiveness. Nonetheless, this therapeutic modality may provoke cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome due to CAR T cell hyperactivation. Additionally, the depletion of most B cells targeted by CD19-directed CAR T cells may lead to insufficient antibody production and increased susceptibility to recurrent infections, although this issue can be mitigated with immunoglobulin supplementation. For individuals with SLE, particularly those with severe disease unresponsive to standard therapies, the potential advantages of CD19-targeted CAR T cell therapy may outweigh the associated risks, warranting further exploration of its long-term safety and effectiveness. In certain systemic autoimmune rheumatic diseases, including RA, the potential risks inherent to CD19-directed CAR T cell therapy may be deemed excessive. Additionally, concerns regarding the potential carcinogenicity associated with CAR T cell therapy have recently emerged [8].

The remarkable efficacy of CAR T cell therapy in patients with SLE suggests that B-cell depletion therapy may hold promise for a significant breakthrough in the treatment of current autoimmune diseases. B cells play a crucial role in the pathogenesis of autoimmune rheumatic diseases, such as SLE, where autoantibodies produced by B cells, including anti-double-stranded DNA antibodies and extractable nuclear antigen antibodies, are associated with disease manifestations. In RA, rheumatoid factors and anti-citrullinated protein antibodies are not only crucial for diagnosis but also correlate with the prognosis of arthritis. Rituximab, an anti-CD20 chimeric monoclonal antibody initially used for treating B-cell lymphoma, represents a classical form of B-cell depletion therapy. By binding to the CD20 antigen on B cells, rituximab can eliminate CD20+ B cells through complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity [9]. Currently, the role of B-cell depletion therapy has been established in the treatment of severe autoimmune rheumatic diseases or those with poor response to other treatments, including RA, anti-neutrophil cytoplasmic antibody-associated vasculitis, and SLE [10-12]. However, the emerging association between belimumab and increased risks of psychiatric adverse events in adult patients with SLE may limit the scope of clinical application of existing treatment modalities [13].

Beyond its B-cell depletion function, rituximab also affects T cells [14]. In most patients with RA treated with rituximab, a significant reduction in T cell concentrations, especially CD4+ T cells, has been observed, correlating with a better treatment response [15, 16]. However, the inability of rituximab to target B cells lacking the CD20 antigen due to late differentiation limits its efficacy. Comparatively, CD19 is more ubiquitously expressed on B cells, and CD19-targeted CAR T cell therapy has shown potential in achieving long-term remission or even cure in autoimmune rheumatic diseases like SLE, making CD19-directed B-cell depletion therapy a promising candidate for future treatments [17]. Blinatumomab, engineered through the Bispecific T-cell engager (BiTE) platform and comprising dual specificity for T cell CD3ε and B cell CD19, exemplifies an innovative approach by facilitating direct cytotoxic T cell engagement with CD19+ B cells without necessitating genetic modification of the patient's T cells or lymphodepleting chemotherapy. Its pharmacological effect duration can be controlled by its half-life, offering the possibility of repeated treatments. Notably, blinatumomab's therapeutic profile, characterized by a reduced risk of severe hematologic toxicity, cytokine-release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) compared to CD19-targeted CAR T cell therapy, underscores its therapeutic promise [18].

A recent clinical trial led by Laura Bucci and her team evaluated blinatumomab's efficacy in a cohort of six individuals with refractory RA, demonstrating significant disease activity reduction and improved clinical outcomes with minimal adverse effects. Blinatumomab was administered intravenously at a regimen of 9 μg/day continuously over a span of 5 days, succeeded by a secondary course after an intermission of 1 week. The monitoring of disease activity was meticulously conducted utilizing the Disease Activity Score in 28 joints (DAS28), in conjunction with ultrasound and fibroblast activation protein inhibitor-based positron emission tomography-computed tomography (FAPI-PET-CT) imaging to evaluate synovitis. The results indicated a noteworthy decline in DAS28 scores from a baseline average of 4.72 to 2.28 post-treatment, signifying a marked reduction in disease activity. Both ultrasound and FAPI-PET-CT imaging corroborated the observed decreases in synovitis. Furthermore, the study documented a significant reduction in the levels of autoantibodies, inclusive of rheumatoid factor and anti-cyclic citrullinated peptide antibodies, indicative of the targeting of antibody-secreting cells, specifically CD19+ plasmablasts, by blinatumomab. Successful attenuation of B cell populations was observed within synovial tissues, which is not attainable with conventional anti-CD20 monoclonal antibody-mediated B cell ablation strategies. The administration of blinatumomab was well-tolerated among the patients, with the occurrence of only mild adverse effects such as mild elevation of body temperature and an elevation in C-reactive protein levels during the initial infusion phase [19]. This trial, along with the inaugural administration of blinatumomab in SSc, as reported by Marion Subklewe and colleagues, highlights the therapeutic potential of BiTE therapy in autoimmune diseases [20] (Table 1).

BiTE therapy offers several advantages, including specific targeting, potential for rapid therapeutic onset, and the ability to overcome mechanisms of resistance inherent to traditional treatments. Furthermore, by mitigating the potential side effects associated with high-dose steroids and chemotherapy, including those affecting growth and reproduction, blinatumomab may offer an advantage in children and young adults. Moreover, the successful treatment experiences of blinatumomab in pediatric leukemia further support the exploration of its role in the treatment of pediatric autoimmune diseases. However, challenges in determining the optimal dosage, managing potential side effects, and ensuring long-term safety remain. Furthermore, the significant cost associated with BiTE therapy presents a barrier to its widespread adoption. Future research endeavors should focus on comprehensive clinical trials to establish the efficacy and safety profile of BiTE therapies across a spectrum of autoimmune diseases. Investigations into combination therapies to enhance treatment efficacy and the identification of biomarkers for patient stratification are crucial in determining those most likely to benefit from BiTE therapy. Additionally, ongoing surveillance to monitor adverse effects and confirm sustained therapeutic benefits is essential. The ongoing quest to revolutionize the treatment paradigm for autoimmune rheumatic diseases, aiming for long-term remission with therapies like blinatumomab, continues to inspire hope and innovation in the medical community.

J.-F.Z., Y.-H.L., S.-W.K., and J.C.-C.W. contributed significantly to the conception, design, and execution of this article. J.-F.Z. and S.-W.K. led the conceptual framework and coordinated the overall structure of the manuscript. Y.-H.L. conducted an extensive review of the literature and provided critical insights into the roles of B cells in autoimmune diseases. J.C.-C.W. contributed to data analysis, interpretation, and the exploration of modern therapeutic strategies. All authors actively participated in drafting, revising, and approving the final manuscript, ensuring the integrity and accuracy of the content.

James Cheng-Chung Wei is the editor-in-chief of the International Journal of Rheumatic Diseases, so he should be excluded from the peer-review process and all editorial decisions related to the acceptance of this article. Publication of this article, and peer-review should be handled independently by other editors to minimize bias. The other authors declare no conflicts of interest.