Harnessing T-cell therapy for lupus nephritis: Opportunities and challenges

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread immune dysregulation and systemic inflammation. Among its many manifestations, lupus nephritis (LN) stands out as one of the most severe and life-threatening complications, affecting up to 60% of SLE patients. LN primarily results from a type III hypersensitivity reaction in which immune complexes are deposited within the kidney. This leads to progressive glomerular and tubulointerstitial lesions compromising renal function. A significant portion of patients presenting with LN will progress to end-stage renal disease (ERSD). Despite advances in treatment strategies, including standard and targeted biologic immunosuppressants, many patients with LN fail to achieve long-term remission, leaving a significant need for safer and more effective therapies. In recent years, T-cell-based therapies have emerged as a promising frontier in the treatment of a variety of conditions including autoimmune diseases. Specifically, chimeric antigen receptor (CAR) T-cell therapies aimed at depleting antibody-producing B cells have demonstrated the ability to restore immune tolerance in several preclinical models of diseases with B-cell-driven pathologies, including SLE. In the case of LN, CAR T-cell therapies have also been deployed in clinical trials to treat patients with refractory disease. The positive results of initial clinical trials provide strong evidence that B-cell-targeted cellular therapies such as CAR T cells targeting B-cell markers CD19 and B-cell maturation antigen (BCMA) might be an effective modality for rebalancing the immune system through the elimination of autoreactive B cells. This review examines the current state of CAR T-cell therapies and their applications in LN by exploring the mechanisms, challenges, and the potential of this unique treatment approach.