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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\u2009weeks. 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\u2009weeks. 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:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06347718?locStr=Erlangen,%20Germany&amp;country=DE&amp;state=Bavaria&amp;city=Erlangen&amp;term=CASTLE&amp;rank=1\" ext-link-type=\"uri\">NCT06347718<\/jats:ext-link>\n                    , EudraCT identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/euclinicaltrials.eu\/search-for-clinical-trials\/?lang=en&amp;EUCT=2024-516819-24-00\" ext-link-type=\"uri\">2022-001366-35<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04185-6","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T10:02:38Z","timestamp":1767780158000},"page":"1142-1151","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["CD19 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Dis."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04185-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04185-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04185-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T15:02:55Z","timestamp":1774018975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04185-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["4185"],"URL":"https:\/\/doi.org\/10.1038\/s41591-025-04185-6","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,7]]},"assertion":[{"value":"30 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"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\u2019s 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\u2019s 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\u2019s 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\u2019s honoraria from Bristol Myers Squibb, Cabaletta, Janssen, Kyverna, Novartis and UCB, which were not related to this study. M.-A.D. has received speaker\u2019s 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.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}