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. 2026 Jan 7.
doi: 10.1038/s41591-025-04185-6. Online ahead of print.

CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial

Fabian Müller #  1   2 , Melanie Hagen #  2   3 , Andreas Wirsching #  2   3 , Soraya Kharboutli  1   2 , Michael Aigner  1   2 , Simon Völkl  1   2 , Sascha Kretschmann  1   2 , Koray Tascilar  2   3 , Jule Taubmann  2   3 , Laura Bucci  2   3 , Maria Gabriella Raimondo  2   3 , Christina Bergmann  2   3 , Tobias Rothe  2   3 , Giulia Corte  2   3 , Carlo Tur  2   3   4 , Luis Muñoz  2   3 , Sebastian Böltz  2   3 , Louis Schuster  2   3 , Fabian Hartmann  2   3 , Panagiotis Garantziotis  2   3 , Silvia Spörl  1   2 , Ingrid Vasova  1   2 , Armin Gerbitz  1   2 , Bernd Spriewald  1   2 , Hans Kiener  5 , Diana Giannarelli  6 , Franco Locatelli  7 , Maria-Antonietta D'Agostino  4   8 , Linda Hanssens  9 , Stefan Miltenyi  9 , Aline Bozec  2   3 , Ricardo Grieshaber-Bouyer  2   3 , Andreas Mackensen #  1   2 , Georg Schett #  10   11   12   13
Affiliations

CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial

Fabian Müller et al. Nat Med. .

Abstract

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 .

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Conflict of interest statement

Competing interests: A.W., S.K., M.A., S.V., S.K., K.T., J.T., L.B., M.G.R., C.B., T.R., C.T., L.M., S.B., L.S., F.H., P.G., S.S., I.V., A.G., B.S., H.K., D.G., F.L. and A.B. declare no conflicts of interest. F.M. has received research support from AstraZeneca, Bristol Myers Squibb, Kite/Gilead and Miltenyi Bioscience; has consulted for AstraZeneca, ArgoBio, Bristol Myers Squibb, CRISPR Therapeutics, EcoR1, Incyte, Janssen, Kite/Gilead, Miltenyi Bioscience, Novartis and Sobi; and has received speaker’s honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Incyte, Janssen, Kite/Gilead, Miltenyi Bioscience, Merck Sharp & Dohme, Novartis, Pfizer, Sobi and Takeda. M.H. has received speaker’s honoraria from Bristol Myers Squibb, AstraZeneca, Century and Lilly, which are not related to this study. S.V. has received research support from Bristol Myers Squibb. A.M. has received speaker’s honoraria from Bristol Myers Squibb, Celgene, Gilead, Janssen, Kite, Miltenyi Biomedicine and Novartis, which were not related to this study. G.S. has received speaker’s honoraria from Bristol Myers Squibb, Cabaletta, Janssen, Kyverna, Novartis and UCB, which were not related to this study. M.-A.D. has received speaker’s honoraria from AbbVie, Bristol Myers Squibb, Lilly, Janssen, Novartis and UCB. L.H. is an employee of Miltenyi Biotec. S.M. is the founder of Miltenyi Biotec. R.G.-B. is co-founder of Epana Bio.

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