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CAR-T cell manufacturing failures and out-of-specification products in the real-world setting: A survey from the EBMT cellular therapy and immunobiology working party

Bone Marrow Transplantation volume 60, pages 1184–1186 (2025)Cite this article

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TO THE EDITOR:

Chimeric antigen receptor (CAR) T-cell therapies have shown significant benefits in the treatment of hematologic malignancies [1,2,3,4,5,6]. Starting in 2018, several anti-CD19 directed CAR-T cells were approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-cell non-Hodgkin’s lymphoma (NHL); a few years later, from 2022, anti-BCMA (B-cell maturation antigen) directed CAR-Ts for the treatment of multiple myeloma (MM) also received marketing authorization from the European Medicines Agency (EMA). CAR-T cell manufacturing failure rates (MF) were reported in pivotal clinical trials, resulting in no CAR-T cell product being available for a various fraction of participating patients. In addition, another fraction of manufacturing processes result in a product that does not comply with pre-defined release criteria (i.e. Out-of-specification products; OOS). In clinical trials, MF has been reported in 4 to 10% of anti-CD19 CAR-T cells, but only in 0 to 1% of anti-BCMA CAR-T cell products [1,2,3,4, 7]. Manufacturing capacities of commercial autologous CAR-T cells have significantly increased since the original marketing approvals, allowing treatment of larger numbers of patients; it can also be postulated that manufacturers have optimized their processes over time. Whether the growing experience in real-world condition has resulted in different rates of MF and OOS products than in registration trials remains however unclear from published reports [8,9,10].

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank the EBMT centers for their participation in the survey (Supplementary Table 3).

Funding

The authors (NW, JEM, JDH, MD, JJT, RR, VV, SB, LLC, EN, RZ, FS, EG, SP, EWD, FC, CC, FM, AR, JK) have no relevant funding to disclose. NW & CC: travel support and speakers fees from BMS Celgene, Janssen, Kite Gilead, Miltenyi and Novartis. AR: Speaker fees from Kite Gilead. JK: research support from Novartis, Miltenyi. Cofounder and shareholder of Gadeta founders and inventor on multiple patents dealing with engineered immune cells. FM received F honoraria from Therakos/Mallinckrodt, Janssen, Sanofi, JAZZ Pharmaceuticals, Gilead, Novartis, Priothera, and Astellas. EG travel support from Kite Gilead; speaker’s bureau from Novartis and Kite Gilead. MD: Travel, Accommodations, Expenses: Kite-Gilead, Novartis, Amgen, Novo Nordisk. Consulting or Advisory Role: Novartis, Alexion Pharma. RR received honoraria from Gilead and Novartis. FS received honoraria from Gilead and travel support from Johnson&Johnson. Emma N: Honorium - KIte/gilead, novartis/J&J, BMS/Celgene, Research grant - KITE/Gilead, DSMB – Autolus VV received honoraria from Gilead/Kite, Novartis, Janssen and BMS Celgene and travel support from Janssen and Gilead/Kite. JJT received honoraria from Gilead and BMS-Celgene.

Author information

Authors and Affiliations

  1. Department of Transfusion Medicine and Cell Therapy, Medical University Vienna, Vienna, Austria

    Nina Worel

  2. EBMT Leiden Study Unit, Leiden, The Netherlands

    Jarl E. Mooyaart & Jorinde D. Hoogenboom

  3. Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, Bern, Switzerland

    Michael Daskalakis

  4. Montpellier University Hospital, Hematology Department, Montpellier, France

    Jean-Jacques Tudesq

  5. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ron Ram

  6. Universitätsklinikum Leipzig, Leipzig, Germany

    Vladan Vucinic

  7. IRCCS Humanitas Research Hospital Milano, Milano, Italy

    Stefania Bramanti

  8. Hospital Clínico, Salamanca, Spain

    Lucía López Corral

  9. Royal Marsden Hospital, London, UK

    Emma Nicholson

  10. University of Freiburg, Freiburg, Germany

    Robert Zeiser

  11. Division of Stem Cell Transplantation and Cellular Immunotherapy, University Hospital Schleswig-Holstein Kiel, Kiel University, Kiel, Germany

    Friedrich Stölzel

  12. Dipartimento di Scienze di Laboratorio ed Ematologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Eugenio Galli

  13. Hematology department, Nancy University Hospital, UMR 7365, CNRS, University of Lorraine, Vandoeuvre-lès-Nancy, France

    Simona Pagliuca

  14. University Medical Center Mainz, Mainz, Germany

    Eva Wagner-Drouet

  15. Princess Maxima Center for pediatric oncology, University Hospital for Children (WKZ), Utrecht, Netherlands

    Friso Calkoen

  16. Institut Paoli-Calmettes Comprehensive Cancer Centre and Module Biothérapies du Centre d’Investigations Cliniques de Marseille, Marseille, France

    Christian Chabannon

  17. Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France

    Florent Malard

  18. San Raffaele Scientific Institute, Hematology and Bone Marrow Transplantation Unit, Milan, Italy

    Annalisa Ruggeri

  19. University Medical Center Utrecht, Utrecht, Netherlands

    Jürgen Kuball

Authors
  1. Nina Worel
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  2. Jarl E. Mooyaart
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Contributions

NW, AR, CC, FM, JK designed the survey; NW, JEM, JDH, AR, CC, FM, JK analyzed the data. NW, AR, CC, FM, JK wrote the manuscript. JEM, JDH, MD, JJT, RR, VV, SB, LLC, EM, RZ, FS, EG, SP, EWD, FG contributed to the article and all authors approved the submitted version.

Corresponding author

Correspondence to Nina Worel.

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Competing interests

The authors declare no funding was received for this study. All authors declare that there are no competing financial interests in relation to the work described.

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Worel, N., Mooyaart, J.E., Hoogenboom, J.D. et al. CAR-T cell manufacturing failures and out-of-specification products in the real-world setting: A survey from the EBMT cellular therapy and immunobiology working party. Bone Marrow Transplant 60, 1184–1186 (2025). https://doi.org/10.1038/s41409-025-02623-0

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