Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Anti-CD19 CAR T cells for pediatric patients with treatment-refractory autoimmune diseases

Nature Medicine (2026)Cite this article

Subjects

Abstract

Chimeric antigen receptor (CAR) T cell therapy was recently proposed as a treatment for adults with B-cell-mediated autoimmune diseases (ADs) refractory to conventional immunomodulatory therapy. We present a case series of eight children with severe/refractory AD (four systemic lupus erythematosus, three dermatomyositis, one systemic sclerosis) treated at Ospedale Pediatrico Bambino Gesù, Rome, and University Hospital Erlangen with a single infusion of 1 × 106 kg−1 point-of-care manufactured autologous CD19 CAR T cells (zorpocabtagene autoleucel), in a hospital exemption (HE) program. In Europe, the HE pathway offers the opportunity to treat patients with life-threatening or seriously debilitating disorders who lack valid therapeutic options, using an advanced therapy medicinal product (ATMP) authorized on a nonroutine, single-patient basis. In contrast to the ‘compassionate use’ pathway, the ATMP does not necessarily need to have undergone clinical trials or marketing authorization applications. Manufacturing was successful in all patients, yielding several drug product bags. Once infused after lymphodepletion, zorpocabtagene autoleucel cells expanded in vivo, promoting prompt B cell clearance. Grade 1 cytokine release syndrome was reported in six patients, and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in one patient. Late-hematotoxicity was limited to grade 1 in two patients. All these adverse events were manageable and no severe infections occurred. With a median follow-up of 16.5 months (range = 9–24 months), all patients experienced a clinically substantial improvement/resolution of AD, as evidenced by reduction in disease activity scores and signs of reversal of organ damage. This improvement enabled sustained discontinuation of immunomodulators, even after B cell reconstitution. The activation of formal clinical trials enrolling children and adolescents is urgently needed to confirm these preliminary results and to assess the long-term safety of this approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Study schema and autologous zorpocabtagene autoleucel DP characterization in pediatric patients with AD.
Fig. 2: Kinetics of expansion, persistence and biodistribution of circulating zorpocabtagene autoleucel cells in pediatric patients with AD.
Fig. 3: Dynamics of CD19+ cells in PB after zorpocabtagene autoleucel infusion, and characterization of the B cell phenotype in patients treated at OPBG.
Fig. 4: Clinical efficacy of autologous zorpocabtagene autoleucel in patients with cSLE, JDM and jSSc.
Fig. 5: Evolution of the disease activity at tissue level after zorpocabtagene autoleucel infusion, across different pediatric ADs.

Data availability

Patient identifiable information cannot be made publicly available for reasons of patient privacy and confidentiality. However, nonidentifiable data are available from the corresponding author upon request, based on specific criteria such as the nature of the research request and the necessary ethical approvals. The estimated time frame for responding to such requests is 2–4 weeks. All data requests will be reviewed in accordance with ethical guidelines. Source data are provided with this paper.

References

  1. Müller, F. et al. CD19 CAR T-cell therapy in autoimmune disease—a case series with follow-up. N. Engl. J. Med. 390, 687–700 (2024).

    Article  PubMed  Google Scholar 

  2. Valenzuela-Almada, M. O. et al. Epidemiology of childhood-onset systemic lupus erythematosus: a population-based study. Arthritis Care Res. 74, 728–732 (2022).

    Article  Google Scholar 

  3. Charras, A., Smith, E. & Hedrich, C. M. Systemic lupus erythematosus in children and young people. Curr. Rheumatol. Rep. 23, 20 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ambrose, N. et al. Differences in disease phenotype and severity in SLE across age groups. Lupus 25, 1542–1550 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Massias, J. S. et al. Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups. Lupus 29, 474–481 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Md Yusof, M. Y. et al. Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope. Rheumatol. Adv. Pract. 7, rkad093 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mendez, E. P. et al. US incidence of juvenile dermatomyositis, 1995–1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum. 49, 300–305 (2003).

    Article  PubMed  Google Scholar 

  8. Lu, X., Peng, Q. & Wang, G. Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress. Nat. Rev. Rheumatol. 20, 48–62 (2024).

    Article  CAS  PubMed  Google Scholar 

  9. Akgün, G. et al. Cardiac evaluation of patients with juvenile dermatomyositis. Pediatr. Res. 97, 333–340 (2025).

    Article  PubMed  Google Scholar 

  10. Volkmann, E. R., Andréasson, K. & Smith, V. Systemic sclerosis. Lancet 401, 304–318 (2023).

    Article  PubMed  Google Scholar 

  11. Foeldvari, I. et al. Best clinical practice in the treatment of juvenile systemic sclerosis: expert panel guidance—the result of the International Hamburg Consensus Meeting December 2022. Expert Rev. Clin. Immunol. 20, 387–404 (2024).

    Article  CAS  PubMed  Google Scholar 

  12. Vasquez-Canizares, N. et al. Developing consensus outcome measures in juvenile systemic sclerosis: a global survey of pediatric rheumatologists and literature review. Pediatr. Rheumatol. Online J. 23, 46 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kim, H. Juvenile dermatomyositis: updates in pathogenesis and biomarkers, current treatment, and emerging targeted therapies. Paediatr. Drugs 27, 57–72 (2025).

    Article  PubMed  Google Scholar 

  14. Northcott, M. et al. Type 1 interferon status in systemic lupus erythematosus: a longitudinal analysis. Lupus Sci. Med. 9, e000625 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Allenbach, Y. et al. Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: study of 121 cases. Neurology 95, e70–e78 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kilinc, O. C. & Ugurlu, S. Clinical features of dermatomyositis patients with anti-TIF1 antibodies: a case based comprehensive review. Autoimmun. Rev. 22, 103464 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Tansley, S. L. et al. Calcinosis in juvenile dermatomyositis is influenced by both anti-NXP2 autoantibody status and age at disease onset. Rheumatology 53, 2204–2208 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hoekstra, E. M. et al. The prognostic power of anti-topoisomerase I and anti-centromere antibodies in systemic sclerosis—a systematic review of the literature. Semin. Arthritis Rheum. 72, 152667 (2025).

    Article  CAS  PubMed  Google Scholar 

  20. Krustev, E., Clarke, A. E. & Barber, M. R. W. B cell depletion and inhibition in systemic lupus erythematosus. Expert Rev. Clin. Immunol. 19, 55–70 (2023).

    Article  CAS  PubMed  Google Scholar 

  21. Merrill, J. T. et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 222–233 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brunner, H. I. et al. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann. Rheum. Dis. 79, 1340–1348 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Evans, L. S. et al. Povetacicept, an enhanced dual APRIL/BAFF antagonist that modulates B lymphocytes and pathogenic autoantibodies for the treatment of lupus and other B cell-related autoimmune diseases. Arthritis Rheumatol. 75, 1187–1202 (2023).

    Article  CAS  PubMed  Google Scholar 

  24. Oddis, C. V. et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 65, 314–324 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ebata, S. et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): open-label extension of a double-blind, investigators-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 4, e546–e555 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Gordon, J. K. et al. Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol. 70, 308–316 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Ramwadhdoebe, T. H. et al. Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis. Rheumatology 58, 1075–1085 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Leandro, M. J. B-cell subpopulations in humans and their differential susceptibility to depletion with anti-CD20 monoclonal antibodies. Arthritis Res. Ther. 15, S3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rider, L. G. et al. 2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects. Rheumatology 56, 1884–1893 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rider, L. G. et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res. 63, S118–S157 (2011).

    Google Scholar 

  31. De Benedetti, F., Diomedi Camassei, F. & Locatelli, F. CAR T-cell therapy in autoimmune disease. N. Engl. J. Med. 390, 1629 (2024).

    PubMed  Google Scholar 

  32. Nicolai, R. et al. Autologous CD19-targeting CAR T cells in a patient with refractory juvenile dermatomyositis. Arthritis Rheumatol. 76, 1560–1565 (2024).

    Article  CAS  PubMed  Google Scholar 

  33. Krickau, T. et al. CAR T-cell therapy rescues adolescent with rapidly progressive lupus nephritis from haemodialysis. Lancet 403, 1627–1630 (2024).

    Article  CAS  PubMed  Google Scholar 

  34. He, X. et al. Treatment of two pediatric patients with refractory systemic lupus erythematosus using CD19-targeted CAR T-cells. Autoimmun. Rev. 24, 103692 (2025).

    Article  CAS  PubMed  Google Scholar 

  35. París-Muñoz, A. et al. CD19 CAR-T cell therapy in a pediatric patient with MDA5+ dermatomyositis and rapidly progressive interstitial lung disease. Med. 6, 100676 (2025).

    Article  PubMed  Google Scholar 

  36. Hanif, M. et al. Contributors to organ damage in childhood lupus: corticosteroid use and disease activity. Rheumatology 64, 3028–3038 (2025).

    Article  CAS  PubMed  Google Scholar 

  37. Del Bufalo, F. et al. Point-of-care fresh CAR T cells for pediatric or young adult BCP-ALL that is relapsed/refractory or in very-high-risk first relapse. Blood Adv. 9, 5091–5102 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Garcia-Prieto, C. A. et al. Epigenetic profiling and response to CD19 chimeric antigen receptor T-cell therapy in B-cell malignancies. J. Natl Cancer Inst. 114, 436–445 (2022).

    Article  PubMed  Google Scholar 

  39. Talleur, A. C. et al. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Blood Adv. 6, 5737–5749 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guzzo, I. et al. Anti-CD19 chimeric antigen receptor T-cell therapy in a highly sensitized patient with focal and segmental glomerulosclerosis. Pediatr. Nephrol. 40, 3513–3519 (2025).

    Article  PubMed  Google Scholar 

  41. Epperly, R. & Shah, N. N. Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL. Hematology Am. Soc. Hematol. Educ. Program 2023, 77–83 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Elsallab, M. et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood 143, 2099–2105 (2024).

    Article  CAS  PubMed  Google Scholar 

  43. Lamble, A. J. et al. Risk of T-cell malignancy after CAR T-cell therapy in children, adolescents, and young adults. Blood Adv. 8, 3544–3548 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Youssef, E., Weddle, K., Zimmerman, L. & Palmer, D. Pharmacovigilance in cell and gene therapy: evolving challenges in risk management and long-term follow-up. Drug Saf. 49, 27–53 (2026).

    Article  PubMed  Google Scholar 

  45. Hayden, P. J. et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann. Oncol. 33, 259–275 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. Müller, F. et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet 401, 815–818 (2023).

    Article  PubMed  Google Scholar 

  47. Tur, C. et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann. Rheum. Dis. 84, 106–114 (2025).

    Article  CAS  PubMed  Google Scholar 

  48. Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat. Med. 28, 2124–2132 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Merkt, W. et al. Persisting CD19.CAR-T cells in combination with nintedanib: clinical response in a patient with systemic sclerosis-associated pulmonary fibrosis after 2 years. Lancet Respir. Med. 13, 651–654 (2025).

    Article  CAS  PubMed  Google Scholar 

  50. Shimizu, M., Nakaseko, H., Muro, Y. & Iwata, N. Effect of abatacept added to mycophenolate mofetil for refractory calcinosis in juvenile dermatomyositis. Mod. Rheumatol. Case Rep. 9, rxaf004 (2025).

    Article  PubMed  Google Scholar 

  51. Aringer, M. et al. European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann. Rheum. Dis. 78, 1151–1159 (2019).

    Article  PubMed  Google Scholar 

  52. Lundberg, I. E. et al. European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann. Rheum. Dis. 76, 1955–1964 (2017).

    Article  PubMed  Google Scholar 

  53. Van den Hoogen, F. et al. Classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747–1755 (2013).

    Article  PubMed  Google Scholar 

  54. Terrault, N. A. et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67, 1560–1599 (2018).

    Article  PubMed  Google Scholar 

  55. Bhattacharya, D., Aronsohn, A., Price, J. & Lo Re, V. Hepatitis C guidance 2023 update: American Association for the Study of Liver Diseases– Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciad319 (2023).

  56. European Union. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. European Union data.europa.eu/eli/reg/2007/1394/oj (2019).

  57. Del Bufalo, F., Quintarelli, C. & Locatelli, F. Allogeneic CAR T cells: a new player in the field and the peculiar opportunities of the Hospital Exemption path. Mol. Ther. 33, 2326–2327 (2025).

    Article  PubMed  Google Scholar 

  58. Ambrosone, A. & Cometa, M. F. Hospital Exemption in Italy: technical-scientific and regulatory aspects in comparison with Europe. Cytotherapy 27, 1251–1261 (2025).

    Article  PubMed  Google Scholar 

  59. Maschan, M. et al. Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients. Nat. Commun. 12, 7200 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Hines, M. R. et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transplant. Cell. Ther. 29, 438 (2023).

    Article  PubMed Central  Google Scholar 

  62. Rejeski, K. et al. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood 142, 865–877 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Gladman, D. D., Ibañez, D. & Urowitz, M. B. Systemic lupus erythematosus disease activity index 2000. J. Rheumatol. 29, 288–291 (2002).

    PubMed  Google Scholar 

  64. Khanna, D. et al. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J. Scleroderma Relat. Disord. 2, 11–18 (2017).

    Article  PubMed  Google Scholar 

  65. La Torre, F. et al. A preliminary disease severity score for juvenile systemic sclerosis. Arthritis Rheum. 64, 4143–4150 (2012).

    Article  PubMed  Google Scholar 

  66. Carsetti, R. et al. Comprehensive phenotyping of human peripheral blood B lymphocytes in healthy conditions. Cytometry A 101, 131–139 (2022).

    Article  PubMed  Google Scholar 

  67. Carsetti, R. et al. Different innate and adaptive immune responses to SARS-CoV-2 infection of asymptomatic, mild, and severe cases. Front. Immunol. 11, 610300 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bagnara, D. et al. A reassessment of IgM memory subsets in humans. J. Immunol. 195, 3716–3724 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The experimental work was supported by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (Ministry of Education, University and Research), including PRIN 2022 (to F.L. and C.Q.), Ricerca Corrente/5×1000 (to F. Del Bufalo and B.D.A.) and RF-2021-12374120 (to C.Q.); Ministero delle Imprese e del Made in Italy (MISE)—POS project Life Science Hub Regione Puglia (to F.L.); F/260019/01/04/X51 (to C.Q.); European Union—Next Generation EU, Mission 4, Component 2, CUP B93D21010860004, National Center for Gene Therapy and Drugs Based on RNA Technology (to F.L.); IMI JU/T2EVOLVE (945393 to F.L.); ‘Hub Life Science–Terapia Avanzata (LSH-TA) PNC-E3-2022-23683269–CUP E83C22006230001 from the Italian Ministry of Health—Piano Nazionale Complementare Ecosistema Innovativo della Salute-cod’ (PNC-E.3 to F.L.); ‘PatENts in tHe medicAl aNd for CompaniEs—ENHANCE’ (to B.D.A.); Deutsche Forschungsgemeinschaft (German Research Foundation)—DFG (TRR221 to G.S.).

We thank Miltenyi Biomedicine for providing the viral supernatant used in the manufacture of zorpocabtagene autoleucel.

Our deepest gratitude goes to all the patients and their families, and to the patient associations that support this research—Associazione ‘Raffaele Passarelli’ Onlus (B.D.A.); Associazione ‘Un … due … tre … Alessio’ (C.Q.); Famiglia Lazzari (C.Q.) and A. Mazza and family (B.D.A.).

Author information

Author notes

  1. These authors contributed equally: Marco Becilli, Markus Metzler, Claudia Bracaglia.

  2. These authors jointly supervised this work: Georg Schett, Fabrizio De Benedetti, Franco Locatelli.

Authors and Affiliations

  1. Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy

    Marco Becilli, Francesca Del Bufalo, Chiara Rosignoli, Pietro Merli, Daria Pagliara, Mattia Algeri, Maria Giuseppina Cefalo, Valentina Bertaina, Matilde Sinibaldi, Giuseppina Li Pira, Monica Gunetti, Biagio De Angelis, Concetta Quintarelli & Franco Locatelli

  2. Department of Paediatrics and Adolescent Medicine, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Markus Metzler, Tobias Krickau & Nora Naumann-Bartsch

  3. Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Markus Metzler, Tobias Krickau, Nora Naumann-Bartsch, Michael Aigner, Simon Völkl, Fabian Müller, Andreas Mackensen & Georg Schett

  4. Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy

    Claudia Bracaglia, Rebecca Nicolai, Emiliano Marasco, Virginia Messia, Antonella Insalaco & Fabrizio De Benedetti

  5. Department of Health Sciences, Magna Graecia University, Catanzaro, Italy

    Mattia Algeri

  6. Advanced Cardiothoracic and Fetal Imaging Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy

    Aurelio Secinaro

  7. Complex Operational Unit (UOC) Pathological Anatomy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy

    Francesca Diomedi Camassei

  8. Department of Internal Medicine 5—Haematology and Oncology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Michael Aigner, Simon Völkl, Fabian Müller & Andreas Mackensen

  9. Transfusion Unit, Department of Laboratories, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Gesù Children’s Hospital, Rome, Italy

    Giovanna Leone

  10. Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Stefan Berg

  11. Miltenyi Biomedicine, Bergisch Gladbach, Germany

    Linda Hanssens

  12. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    Concetta Quintarelli

  13. Department of Internal Medicine 3—Rheumatology and Immunology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Georg Schett

  14. Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy

    Franco Locatelli

Authors
  1. Marco Becilli
    View author publications

    Search author on:PubMed Google Scholar

  2. Markus Metzler
    View author publications

    Search author on:PubMed Google Scholar

  3. Claudia Bracaglia
    View author publications

    Search author on:PubMed Google Scholar

  4. Rebecca Nicolai
    View author publications

    Search author on:PubMed Google Scholar

  5. Tobias Krickau
    View author publications

    Search author on:PubMed Google Scholar

  6. Francesca Del Bufalo
    View author publications

    Search author on:PubMed Google Scholar

  7. Chiara Rosignoli
    View author publications

    Search author on:PubMed Google Scholar

  8. Emiliano Marasco
    View author publications

    Search author on:PubMed Google Scholar

  9. Nora Naumann-Bartsch
    View author publications

    Search author on:PubMed Google Scholar

  10. Virginia Messia
    View author publications

    Search author on:PubMed Google Scholar

  11. Pietro Merli
    View author publications

    Search author on:PubMed Google Scholar

  12. Daria Pagliara
    View author publications

    Search author on:PubMed Google Scholar

  13. Mattia Algeri
    View author publications

    Search author on:PubMed Google Scholar

  14. Aurelio Secinaro
    View author publications

    Search author on:PubMed Google Scholar

  15. Maria Giuseppina Cefalo
    View author publications

    Search author on:PubMed Google Scholar

  16. Francesca Diomedi Camassei
    View author publications

    Search author on:PubMed Google Scholar

  17. Valentina Bertaina
    View author publications

    Search author on:PubMed Google Scholar

  18. Matilde Sinibaldi
    View author publications

    Search author on:PubMed Google Scholar

  19. Antonella Insalaco
    View author publications

    Search author on:PubMed Google Scholar

  20. Michael Aigner
    View author publications

    Search author on:PubMed Google Scholar

  21. Giovanna Leone
    View author publications

    Search author on:PubMed Google Scholar

  22. Giuseppina Li Pira
    View author publications

    Search author on:PubMed Google Scholar

  23. Monica Gunetti
    View author publications

    Search author on:PubMed Google Scholar

  24. Stefan Berg
    View author publications

    Search author on:PubMed Google Scholar

  25. Biagio De Angelis
    View author publications

    Search author on:PubMed Google Scholar

  26. Simon Völkl
    View author publications

    Search author on:PubMed Google Scholar

  27. Linda Hanssens
    View author publications

    Search author on:PubMed Google Scholar

  28. Fabian Müller
    View author publications

    Search author on:PubMed Google Scholar

  29. Andreas Mackensen
    View author publications

    Search author on:PubMed Google Scholar

  30. Concetta Quintarelli
    View author publications

    Search author on:PubMed Google Scholar

  31. Georg Schett
    View author publications

    Search author on:PubMed Google Scholar

  32. Fabrizio De Benedetti
    View author publications

    Search author on:PubMed Google Scholar

  33. Franco Locatelli
    View author publications

    Search author on:PubMed Google Scholar

Contributions

M.B., M.M. and C.B. designed the treatments and analyses, clinically managed the patients, participated in the data collection, interpreted and analyzed the data, and wrote the paper. G.S., F. De Benedetti and F.L. designed the treatments and analyses, supervised the project conduction and the clinical management of the patients, interpreted and analyzed the data, and wrote the paper. R.N., T.K., F. Del Bufalo, C.R., E.M., N.N.‑B., V.M., P.M., D.P., M. Algeri, A.I., S.B., F.M. and A.M. clinically managed the patients, participated in the data collection, and interpreted and analyzed the data. A.S. performed and interpreted the radiological images. M.G.C. supervised the regulatory activities for the conduct of the HE program. F.D.C. performed pathological examinations of kidney biopsies. V.B. performed the flow-cytometry analyses of B cell reconstitution and B cell subsets. M.S. and S.V. performed patients’ immune monitoring. M. Aigner and M.G. manufactured the CAR T cells. G.L. performed apheresis collection. G.L.P. performed apheresis manipulation. B.D.A. and C.Q. supervised all the immune-monitoring studies, interpreted and analyzed the data, and wrote the paper. L.H. contributed vital reagents. All authors reviewed the paper for final approval before submission.

Corresponding author

Correspondence to Franco Locatelli.

Ethics declarations

Competing interests

M.M. has participated in advisory boards for Novartis. T.K. has received consulting fees from Novartis and Pfizer; speaker honoraria from Novartis, Pfizer and Kyowa Kirin; and meeting support from Pfizer, Novartis and AbbVie. P.M. reports personal fees from Sobi, Miltenyi and Amgen. M. Aigner has received research grants from Miltenyi Biotec and Kyverna; consulting fees from Miltenyi Biotec; speaker honoraria from Miltenyi Biotec and Raumedic; expert testimony payments from RUHR‑IP; travel support from Miltenyi Biotec and material support from Miltenyi Biotec. S.V. has received research support from the Interdisciplinary Center for Clinical Research at University Hospital Erlangen‑Nuremberg (grant D43). L.H. is an employee of Miltenyi Biomedicine. F.M. has received research grants from Kite/Gilead; consulting fees from AbbVie, ArgoBio, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Janssen, Kite and Novartis; speaker honoraria from AbbVie, ArgoBio, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Janssen, Kite, Kyverna, Miltenyi Biomedicine, Novartis and Sobi; has served on an advisory board for Bristol Myers Squibb and received research funding from Deutsche Krebshilfe (grant 0113695). A.M. has received research grants from Miltenyi Biomedicine and Kyverna; consulting fees from BMS/Celgene, Kite/Gilead, Novartis, BioNTech, Miltenyi Biomedicine and Century Therapeutics; speaker honoraria from BMS/Celgene, Kite/Gilead, Novartis and Miltenyi Biomedicine; and meeting support from AbbVie and Janssen. G.S. has received speaker honoraria from Novartis, Bristol Myers Squibb, Kyverna and Cabaletta. F. De Benedetti declares unrestricted research grants from Sobi, Sanofi, Regeneron, Roche, Elixiron and Novartis; participation on the Data Safety Monitoring Board for Regeneron and consulting fees from Sobi, Novartis and Apollo. F.L. serves on the scientific advisory board of Amgen, Novartis, Sanofi and Vertex; and speaker’s bureau for Miltenyi Biomedicine, Amgen, Novartis, Bristol Myers Squibb, Gilead, MEDAC and Sobi. The other authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Shaun Jackson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Memory profile of the CD4+ and CD8+ cells in the leukapheresis, as assessed by flow cytometry.

Multiparametric flow-cytometry analysis of the starting materials collected from OPBG patients to characterize the memory profile of CD4+ and CD8+ T cells. Proportion of naive (CCR7+/CD45RO− and CD62L+/CD45RA+), central memory (CM, CCR7+/CD45RO+), effector memory (EM, CCR7−/CD45RO+), and terminally differentiated effector memory re-expressing CD45RA (TEMRA, CCR7−/CD45RO−) cells among CD4+ (upper plot) and CD8+ T cells (lower plot).

Source data

Extended Data Fig. 2 In vivo memory profile of zorpocabtagene-autoleucel cells in peripheral blood (PB) and bone marrow (BM).

Distribution of ‘naive’, central memory (CM), effector memory (EM) T cells, and terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA) in the CD4+CAR+ and CD8+CAR+ T cells in PB (a) and in BM (b), according to different time points after zorpocabtagene-autoleucel infusion. BM samples were collected only in OPBG patients. Each dot represents an individual evaluable patient. Boxes represent the first quartile, median and forth quartile distribution, and boundaries of lower and upper whiskers showing minimum to maximum values.

Source data

Extended Data Fig. 3 CAR− T-cell reconstitution, along with CD4+:CD8+ ratio, at different time points after zorpocabtagene-autoleucel infusion.

CAR− T cell reconstitution is shown with granular data from individual patients (upper panel). The distribution of CD4+ and CD8+ T cells is depicted as box and whiskers plots in the middle panel (all patients) and lower panel (excluded cSLE-OPBG003), according to different time points, with each dot indicating an individual value from a single patient, boxes representing first quartile, median and forth quartile distribution, and boundaries of lower and upper whiskers showing minimum to maximum values. CD3+CAR− cells recovered in all patients starting from week 4 after lymphodepletion. Both CD4+CAR− and CD8+CAR− increased over time, with a homogeneous distribution in all patients but cSLE-OPBG003 (lower panel). Indeed, in this patient, CD3+CAR− cells achieved significantly higher levels compared to other patients starting from month 6 after zorpocabtagene-autoleucel infusion, with a predominance of CD8+ cells. Importantly, CAR gene copies were persistently undetectable in peripheral blood from month 3 throughout the follow-up. A lymphoproliferative disease was excluded. W: week. M: month.

Source data

Extended Data Fig. 4 Characterization of the plasma cells (PCs) in the bone marrow of OPBG patients, as assessed by multiparametric flow-cytometry.

Percentage of bone marrow PCs expressing CD19+38high138−, 19+38high138+ and CD19−38high138+ are depicted for each OPBG patient, according to different time points. Bone marrow aspirate was not performed before treatment in patient cSLE-OPBG001, and the sample was not available at month 12 for patient JDM-OPBG002.

Source data

Extended Data Fig. 5 Key cytokine levels in serum samples collected at different time points.

a, Box plot representing the peak levels of IFN-γ, IL-10, IL-6 and TNF. The higher levels of IL-6 refer to patient JDM-OPBG004 and cSLE-FAU001. Individual values derived from individual patients are reported, with boxes representing first quartile, median and forth quartile distribution. Boundaries of lower and upper whiskers show minimum and maximum values. Grade 1 cytokine release syndrome occurred in both patients, while grade 1 immune effector cell-associated neurotoxicity syndrome was experienced by JDM-OPBG004. Tocilizumab was administered to cSLE-FAU001 on day 5. Highest levels of IFN-γ, IL-10 and TNF have been shown in patient JDM-OPBG004. b, Evolution of serum levels of IL-6, IFN-γ, TNF and IL-10 in all patients infused with zorpocabtagene-autoleucel. Serum IL-10 levels were systematically studied only in patients treated at OPBG.

Source data

Extended Data Fig. 6 Evolution of C-reactive protein (CRP) and ferritin over time, after zorpocabtagene-autoleucel infusion.

a,b, Spaghetti plot representing the evolution of the CRP (a) and ferritin (b) in each patient treated with zorpocabtagene-autoleucel, over the first 4 weeks after infusion. Horizontal straight lines represent the period during which cytokine release syndrome manifested.

Source data

Extended Data Fig. 7 Evolution of IgG, IgA and IgM over time, according to different time points, before and after zorpocabtagene-autoleucel infusion.

The evolution of IgG, IgA and IgM levels is shown individually for each patient, according to available data at different time points. The vertical black dotted line indicates the zorpocabtagene-autoleucel infusion, while the horizontal red dotted lines represent the lower limit of normal values for each type of immunoglobulin.

Source data

Extended Data Fig. 8

Hematotoxicity after zorpocabtagene-autoleucel infusion. Representation of early and late immune effector cell-associated hematotoxicity (ICAHT)62 in each patient treated with autologous zorpocabtagene-autoleucel.

Source data

Extended Data Table 1 Characterization of the starting materials across patients undergoing lymphocyte collection at OPBG (OPBG001-005) and at FAU (FAU001-003)
Full size table
Extended Data Table 2 Safety profile of zorpocabtagene-autoleucel in childhood-onset autoimmune diseases
Full size table

Supplementary information

Supplementary Information

Supplementary Tables 1–4 and Figs. 1–4.

Reporting Summary

Supplementary Data

Supporting data for Supplementary Figs. 2 and 3.

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Becilli, M., Metzler, M., Bracaglia, C. et al. Anti-CD19 CAR T cells for pediatric patients with treatment-refractory autoimmune diseases. Nat Med (2026). https://doi.org/10.1038/s41591-025-04191-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41591-025-04191-8

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing