CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial
Summary
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
Content
# CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial
*Published: 2026 Mar*
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 .
DOI: 10.1038/s41591-025-04185-6