Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04185-6
Fabian Müller, Melanie Hagen, Andreas Wirsching, Soraya Kharboutli, Michael Aigner, Simon Völkl, Sascha Kretschmann, Koray Tascilar, Jule Taubmann, Laura Bucci, Maria Gabriella Raimondo, Christina Bergmann, Tobias Rothe, Giulia Corte, Carlo Tur, Luis Muñoz, Sebastian Böltz, Louis Schuster, Fabian Hartmann, Panagiotis Garantziotis, Silvia Spörl, Ingrid Vasova, Armin Gerbitz, Bernd Spriewald, Hans Kiener, Diana Giannarelli, Franco Locatelli, Maria-Antonietta D’Agostino, Linda Hanssens, Stefan Miltenyi, Aline Bozec, Ricardo Grieshaber-Bouyer, Andreas Mackensen, Georg Schett
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 .
{"title":"CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial","authors":"Fabian Müller, Melanie Hagen, Andreas Wirsching, Soraya Kharboutli, Michael Aigner, Simon Völkl, Sascha Kretschmann, Koray Tascilar, Jule Taubmann, Laura Bucci, Maria Gabriella Raimondo, Christina Bergmann, Tobias Rothe, Giulia Corte, Carlo Tur, Luis Muñoz, Sebastian Böltz, Louis Schuster, Fabian Hartmann, Panagiotis Garantziotis, Silvia Spörl, Ingrid Vasova, Armin Gerbitz, Bernd Spriewald, Hans Kiener, Diana Giannarelli, Franco Locatelli, Maria-Antonietta D’Agostino, Linda Hanssens, Stefan Miltenyi, Aline Bozec, Ricardo Grieshaber-Bouyer, Andreas Mackensen, Georg Schett","doi":"10.1038/s41591-025-04185-6","DOIUrl":"https://doi.org/10.1038/s41591-025-04185-6","url":null,"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: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"https://clinicaltrials.gov/study/NCT06347718?locStr=Erlangen,%20Germany&country=DE&state=Bavaria&city=Erlangen&term=CASTLE&rank=1\" ext-link-type=\"uri\">NCT06347718</jats:ext-link> , EudraCT identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-516819-24-00\" ext-link-type=\"uri\">2022-001366-35</jats:ext-link> .","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"18 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04097-5
Ana van Lieshout Titan, Peter J. Dodd, Ted Cohen, Nicolas A. Menzies
{"title":"Estimating the number of incorrect tuberculosis diagnoses in low- and middle-income countries","authors":"Ana van Lieshout Titan, Peter J. Dodd, Ted Cohen, Nicolas A. Menzies","doi":"10.1038/s41591-025-04097-5","DOIUrl":"https://doi.org/10.1038/s41591-025-04097-5","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"42 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04094-8
Suhana Bedi, Jason Alan Fries, Nigam H. Shah
{"title":"How to interpret ‘zero-shot’ results from generative EHR models","authors":"Suhana Bedi, Jason Alan Fries, Nigam H. Shah","doi":"10.1038/s41591-025-04094-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04094-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"43 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04067-x
Carolina Alves Costa Silva, Marc Machaalani, Renee Maria Saliby, Caiwei Zhong, Wanling Xie, Edoardo Pasolli, Gianmarco Piccinno, Cécile Dalban, Marine Fidelle, Aurelia Meurisse, Dewi Vernerey, Gwo-Shu Mary Lee, Roxanne Birebent, Eddy Saad, Clara Steiner, Ronan Flippot, Janice Barros-Monteiro, Nicola Segata, Antoine Thiery-Vuillemin, Silvia Formenti, Tatiana Kuznetsova, Bernard Escudier, Lisa Derosa, Laurence Zitvogel, Toni K. Choueiri, Laurence Albiges
{"title":"Soluble MAdCAM-1 as a biomarker in metastatic renal cell carcinoma","authors":"Carolina Alves Costa Silva, Marc Machaalani, Renee Maria Saliby, Caiwei Zhong, Wanling Xie, Edoardo Pasolli, Gianmarco Piccinno, Cécile Dalban, Marine Fidelle, Aurelia Meurisse, Dewi Vernerey, Gwo-Shu Mary Lee, Roxanne Birebent, Eddy Saad, Clara Steiner, Ronan Flippot, Janice Barros-Monteiro, Nicola Segata, Antoine Thiery-Vuillemin, Silvia Formenti, Tatiana Kuznetsova, Bernard Escudier, Lisa Derosa, Laurence Zitvogel, Toni K. Choueiri, Laurence Albiges","doi":"10.1038/s41591-025-04067-x","DOIUrl":"https://doi.org/10.1038/s41591-025-04067-x","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"391 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04108-5
Alyssa J. Moran, Neha Khandpur, Christina A. Roberto
{"title":"Identifying ultra-processed foods for policy","authors":"Alyssa J. Moran, Neha Khandpur, Christina A. Roberto","doi":"10.1038/s41591-025-04108-5","DOIUrl":"https://doi.org/10.1038/s41591-025-04108-5","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"20 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04127-2
Marco Proietti, Giulio Francesco Romiti
{"title":"Understanding the link between atrial fibrillation and cognitive decline","authors":"Marco Proietti, Giulio Francesco Romiti","doi":"10.1038/s41591-025-04127-2","DOIUrl":"https://doi.org/10.1038/s41591-025-04127-2","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04159-8
Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans-Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan-Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje Vick, Irmela Jeremias, Wolfgang E Berdel, Klaus Hansen, Arthur Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow
{"title":"Author Correction: Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.","authors":"Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans-Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan-Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje Vick, Irmela Jeremias, Wolfgang E Berdel, Klaus Hansen, Arthur Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow","doi":"10.1038/s41591-025-04159-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04159-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41591-025-04130-7
Mary E. Rinella, Arun J. Sanyal, Rohit Loomba, Mazen Noureddin, Meena B. Bansal, Philip N. Newsome, Vlad Ratziu
{"title":"MASLD as a complication of obesity must include liver risk stratification","authors":"Mary E. Rinella, Arun J. Sanyal, Rohit Loomba, Mazen Noureddin, Meena B. Bansal, Philip N. Newsome, Vlad Ratziu","doi":"10.1038/s41591-025-04130-7","DOIUrl":"https://doi.org/10.1038/s41591-025-04130-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"13 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1038/s41591-025-04153-0
Irene Paassen, Mark A. Rubin
{"title":"Going beyond genomics in precision oncology","authors":"Irene Paassen, Mark A. Rubin","doi":"10.1038/s41591-025-04153-0","DOIUrl":"https://doi.org/10.1038/s41591-025-04153-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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