CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial.
Level 4 - case-series / case-control
Uncontrolled phase 1/2a single-arm basket trial
PubMed 41501497 · doi:10.1038/s41591-025-04185-6
What was done
This phase 1/2a two-stage basket trial (CASTLE) evaluated the safety and efficacy of zorpocabtagene autoleucel (Zorpo-cel, MB-CART19.1), an autologous CD19 CAR-T cell product, in 24 patients with treatment-resistant autoimmune diseases (10 with systemic lupus erythematosus [SLE], 9 with systemic sclerosis [SSc], and 5 with idiopathic inflammatory myopathies [IIM]). Participants stopped baseline immunosuppressants, received standard lymphodepletion with fludarabine and cyclophosphamide, and were given a single CAR-T cell infusion. Primary safety endpoints were rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Secondary efficacy endpoints evaluated at 24 weeks included DORIS remission (SLE), arrest of interstitial lung disease progression (SSc), and American College of Rheumatology major/moderate response (IIM).
What was found
No CRS higher than grade 2 and no ICANS events were observed. At 24 weeks, 22 of 24 patients achieved their predefined clinical efficacy endpoints: 9 of 10 with SLE achieved DORIS remission, 9 of 9 with SSc showed no lung disease progression, and 4 of 5 with IIM met ACR major/moderate response criteria. All 24 patients remained completely off glucocorticoids and other immunosuppressive therapies throughout the 24-week follow-up.
Why it matters
These findings suggest that CD19 CAR-T cell therapy is safe and feasible across multiple severe, refractory autoimmune conditions, achieving short-term drug-free remission and supporting progression to larger pivotal trials.
Limits
The trial is limited by a small sample size (subgroups of 5 to 10 patients), an open-label single-arm design lacking a randomized or concurrent control group, and a short 24-week follow-up window that cannot establish long-term remission durability or late adverse effects.