Sebastian Böltz

To the Editor: Systemic lupus erythematosus (SLE) is a severe autoimmune disease that predominantly affects young women. SLE is characterized by the formation of autoantibodies and immune complex-mediated inflammation and organ damage. Although autoreactive B cells play a key role in the pathogenesis of SLE, B-cell depletion by antibodies has only limited therapeutic efficacy. 1 This paradox has been attributed to the inaccessibility and persistence of autoreactive B cells within lymphatic organs and inflamed tissues 2 or the pathologic role of CD20-negative plasma cells, which may act as an additional source of autoantibodies in patients with SLE. 3 Chimeric antigen receptor (CAR)-modified T cells that have been genetically engineered to recognize CD19 and other B-cell surface antigens have emerged as a powerful tool for the treatment of relapsed or refractory B-cell cancers. 4 This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, 5 provides a rationale for the use of CAR T-cell therapies in patients with SLE.

Chimeric antigen receptor (CAR)-T cells are considered a powerful therapeutic tool to reset the immune system in patients with autoimmune diseases. Innovative trial designs are needed to allow feasible testing of the safety and efficacy of CAR-T cells in clinical studies. CASTLE (CAR-T cells in systemic B cell mediated autoimmune disease) is a phase 1/2a two-stage optimal design basket study that investigated the safety and efficacy of zorpocabtagene autoleucel (Zorpo-cel, also known as MB-CART19.1), an autologous CD19 CAR-T cell product, in patients with treatment-resistant systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM). The primary safety outcome was the rate of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The secondary clinical efficacy outcomes were remission of SLE according to DORIS criteria, no progression of interstitial lung disease in SSc and American College of Rheumatology (ACR) major/moderate response in IIM after 24 weeks. A total of 24 patients were enrolled (10 with SLE, 9 with SSc and 5 with IIM), all receiving a single infusion of Zorpo-cel after stopping immunosuppressive treatments and receiving standard lymphodepletion with cyclophosphamide and fludarabine. Primary and secondary endpoints of CASTLE were met. Regarding safety, no CRS higher than grade 2 and no ICANS occurred. Regarding efficacy, 22 of the 24 patients achieved predefined efficacy endpoints, with 9 out of 10 patients with SLE reaching DORIS remission, 9 out of 9 patients with SSc showing no disease progression, and 4 out of 5 patients with IIM reaching ACR major/moderate response. Furthermore, all patients remained free of glucocorticoids and any other immunosuppressive treatment over the entire observation period of 24 weeks. CASTLE suggests the feasibility, safety and efficacy of Zorpo-cel in three different autoimmune diseases and paves the way for conducting a pivotal study. ClinicalTrials.gov identifier: NCT06347718 , EudraCT identifier: 2022-001366-35 .