Published on March 23, 2026
CD19 CAR-T Cells for Treatment-refractory Autoimmune Diseases: The Phase 1/2 CASTLE Basket Trial
by Alex Khadhim
Researchers at Friedrich-Alexander-Universität Erlangen–Nürnberg and Universitätsklinikum Erlangen have found that autologous CD19 CAR T cell therapy can induce rapid, drug-free clinical responses across several severe, treatment-refractory autoimmune diseases. These findings, published in Nature Medicine as a report of the CASTLE phase 1/2a basket trial, demonstrate that a single infusion of CD19 CAR T cells (Zorpo-cel) produced high response rates in systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myopathies, alongside evidence of a profound but transient B cell depletion consistent with immune “resetting.” The core concept of these results is that cellular immunotherapy, previously dominated by oncology indications, may be capable of inducing broad, sustained autoimmune disease control after one treatment in carefully selected, heavily pretreated patients.
The study addresses an unmet need in patients with multi-organ autoimmunity who remain active despite extensive immunosuppression and B cell–directed biologics. Conventional B cell depletion can be incomplete, transient, and requires repeated dosing, while long-term immunosuppression carries cumulative toxicity. CASTLE used a structured two-stage phase 1/2a design incorporating both safety and efficacy requirements and enrolled 24 adults (10 lupus, nine systemic sclerosis, five inflammatory myopathy) with substantial prior treatment failure or intolerance (median four regimens) and clinically active disease at baseline. Immunosuppressive medications were stopped before leukapheresis, limited bridging with low-dose prednisolone was permitted, and patients received a fixed CAR T cell dose followed by standardized safety surveillance, disease-specific composite efficacy endpoints at 6 months, and longitudinal immune profiling to link cellular kinetics with clinical outcomes.
Overall, 22 of 24 participants met the prespecified 6-month efficacy endpoint, corresponding to an overall response rate of 87.5% (90% CI 65.6–97.7). CAR T cells expanded with a median peak of 140 cells/µl around day 10 and became undetectable after a median of 83 days. B cells were eliminated quickly (median 7 days), with median B cell aplasia lasting 83 days; four patients had not reconstituted B cells by 6 months. Toxicities were predominantly low grade: cytokine release syndrome occurred in 71% (grade 2 in 4%, with no grade 3–4 events), 58% received tocilizumab, and there were no cases of ICANS. Cytopenias were generally transient, with median durations of grade ≥3 leukopenia and neutropenia of 14 days and lymphopenia of 10 days. These results are important as they provide early clinical evidence that CD19 CAR T cells can deliver deep, medication-free disease control across multiple autoimmune indications with a manageable safety profile, supporting larger studies to define durability, patient selection, and long-term immune consequences.
Reference:
Müller F, Hagen M, Wirsching A, et al. CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial. Nat Med. Published online January 7, 2026.
http://doi.org/10.1038/s41591-025-04185-6
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