Dual-targeting chimeric antigen receptor T-cell therapy achieves prolonged remission in refractory systemic lupus erythematosus
Chimeric antigen receptor T-cell (CAR-T) therapy, a mainstay in the management of B-cell malignancies, is rapidly emerging as a transformative approach for severe autoimmune diseases, particularly systemic lupus erythematosus (SLE). While B-cell–directed therapies have demonstrated sustained efficacy in multiple autoantibody-mediated disorders, conventional approaches often show limited and transient benefit in SLE, underscoring the need for innovative strategies.
A recent study published in the Journal of Hematology & Oncology reports that dual-targeted BCMA-CD19 armored CAR-T therapy induced stringent complete remission in the majority of patients with refractory SLE, with responses sustained for up to six years.
SLE and its renal manifestation, lupus nephritis (LN), are driven by pathogenic autoantibodies produced by CD19-positive B cells and BCMA-expressing plasma cells, including long-lived plasma cells (LLPCs). While CD19-directed CAR-T therapy can induce a profound immune reset, relapse remains a challenge due to the persistence of antigen-negative or anatomically protected LLPCs. Relapses after CD19 CAR-T therapy have shown responsiveness to plasma cell–directed interventions, supporting the rationale for broader targeting of the humoral immune compartment to enhance long-term efficacy.
In the reported trial, 12 patients with refractory SLE, including 10 with biopsy-proven LN, received ICG318, a dual-targeting BCMA-CD19 armored CAR-T therapy designed to eliminate both CD19-positive B cells and BCMA-positive plasma cells, including LLPCs. This approach specifically addressed the limitation of CD19 CAR-T monotherapy, which, while promising, was associated with relapses driven by persistent CD19-negative plasma cells.
Outcomes were remarkable. Ten of 12 patients achieved stringent complete remission, defined as medication-free DORIS complete remission with complete renal response. Drug-free serological complete remission was observed in 11 patients. Repeat renal biopsies in nine patients demonstrated significant histological improvement, including clearance of immune-complex deposits and resolution of chronic glomerular injury.
The therapy was well tolerated. No high-grade cytokine release syndrome or neurotoxicity was reported. Spontaneous pregnancies occurred post-treatment, resulting in healthy full-term births, though further study is warranted to evaluate long-term fertility outcomes. The durability of stringent complete remission, approaching six years, highlights the potential for long-term disease control in humoral autoimmune disorders using CAR-T therapy. These findings provide compelling evidence that dual-targeted approaches may overcome limitations of earlier CAR-T strategies, offering hope for sustained remission in refractory SLE.
References
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