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.

  • Perspective
  • Published:

A guide to the collection of T-cells by apheresis for ATMP manufacturing—recommendations of the GoCART coalition apheresis working group

Bone Marrow Transplantation volume 58, pages 742–748 (2023)Cite this article

Subjects

Abstract

Autologous chimeric antigen receptor-modified T-cells (CAR-T) provide meaningful benefit for otherwise refractory malignancies. As clinical indications for CAR-T cells are expanding, hospitals hitherto not active in the field of immune effector cell therapy will need to build capacity and expertise. The GoCART Coalition seeks to disseminate knowledge and skills to facilitate the introduction of CAR-T cells and to standardize management and documentation of CAR-T cell recipients, in order to optimize outcomes and to be able to benchmark clinical results against other centers. Apheresis generates the starting material for CAR-T cell manufacturing. This guide provides some initial suggestions for patient’s apheresis readiness and performance to collect starting material and should thus facilitate the implementation of a CAR-T-starting material apheresis facility. It cannot replace, of course, the extensive training needed to perform qualitative apheresis collections in compliance with national and international regulations and assess their cellular composition and biological safety.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Apherithmetic describes the formulas used in a leukapheresis procedure.

Similar content being viewed by others

Notes

  1. Collection efficiency (CE) is the fraction of the circulating cells that is extracted during apheresis and takes into consideration the cell concentration in the peripheral blood, processed blood volume and number of collected cells. CE1 uses the mean of pre- and post- target cell concentrations in the peripheral blood whereas CE2 uses only the pre-apheresis concentration of target cells.

References

  1. Chabannon C, Bonini C. Structure of and signalling through chimeric antigen receptor. In: Kroger N, Gribben J, Chabannon C, Yakoub-Agha I, Einsele H (eds). The EBMT/EHA CAR-T Cell Handbook: Cham (CH), 2022, pp 3–5.

  2. Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol. 2021;18:715–27. https://doi.org/10.1038/s41571-021-00530-z.

    Article  CAS  PubMed  Google Scholar 

  3. Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021;21:145–61. https://doi.org/10.1038/s41568-020-00323-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Leick MB, Maus MV, Frigault MJ. Clinical perspective: treatment of aggressive B cell lymphomas with FDA-approved CAR-T cell therapies. Mol Ther. 2021;29:433–41. https://doi.org/10.1016/j.ymthe.2020.10.022.

    Article  CAS  PubMed  Google Scholar 

  5. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18:71–84. https://doi.org/10.1038/s41571-020-0427-6.

    Article  CAS  PubMed  Google Scholar 

  6. Frigault MJ, Maus MV. State of the art in CAR T cell therapy for CD19+ B cell malignancies. J Clin Invest. 2020;130:1586–94. https://doi.org/10.1172/JCI129208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. DiNofia AM, Maude SL. Chimeric antigen receptor T-cell therapy clinical results in pediatric and young adult B-ALL. Hemasphere. 2019;3:e279 https://doi.org/10.1097/HS9.0000000000000279.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bucklein VL, et al. CD19-CAR-T cells are an effective therapy of post-transplant relapse in B- ALL patients: Real-World Data from Germany. Blood Adv. 2023. e-pub ahead of print 20230106; https://doi.org/10.1182/bloodadvances.2022008981.

  9. Das RK, Vernau L, Grupp SA, Barrett DM. Naive T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Disco. 2019;9:492–9. https://doi.org/10.1158/2159-8290.CD-18-1314.

    Article  CAS  Google Scholar 

  10. Myers RM, Shah NN, Pulsipher MA. How we use risk factors for success or failure of CD19 CAR T-cells to guide management of children/AYA with B-cell ALL. Blood. 2022. e-pub ahead of print 20221123; https://doi.org/10.1182/blood.2022016937.

  11. Iacoboni G, Rejeski K, Villacampa G, van Doesum JA, Chiappella A, Bonifazi F, et al. Real-world evidence of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2022;6:3606–10. https://doi.org/10.1182/bloodadvances.2021006922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4:5414–24. https://doi.org/10.1182/bloodadvances.2020003092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gafter-Gvili A, Polliack A. Bendamustine associated immune suppression and infections during therapy of hematological malignancies. Leuk Lymphoma. 2016;57:512–9. https://doi.org/10.3109/10428194.2015.1110748.

    Article  CAS  PubMed  Google Scholar 

  14. Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Durig J, et al. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018;36:2395–404. https://doi.org/10.1200/JCO.2017.76.8960.

    Article  CAS  PubMed  Google Scholar 

  15. Danylesko I, Chowers G, Shouval R, Besser MJ, Jacoby E, Shimoni A, et al. Treatment with anti CD19 chimeric antigen receptor T cells after antibody-based immunotherapy in adults with acute lymphoblastic leukemia. Curr Res Transl Med. 2020;68:17–22. https://doi.org/10.1016/j.retram.2019.12.001.

    Article  PubMed  Google Scholar 

  16. Pillai V, Muralidharan K, Meng W, Bagashev A, Oldridge DA, Rosenthal J, et al. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy. Blood Adv. 2019;3:3539–49. https://doi.org/10.1182/bloodadvances.2019000692.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hayden PJ, Roddie C, Bader P, Basak GW, Bonig H, Bonini C, 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. 2022;33:259–75. https://doi.org/10.1016/j.annonc.2021.12.003.

    Article  CAS  PubMed  Google Scholar 

  18. Amini L, Silbert SK, Maude SL, Nastoupil LJ, Ramos CA, Brentjens RJ, et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion. Nat Rev Clin Oncol. 2022;19:342–55. https://doi.org/10.1038/s41571-022-00607-3.

    Article  PubMed  Google Scholar 

  19. Acharya UH, Dhawale T, Yun S, Jacobson CA, Chavez JC, Ramos JD, et al. Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy. Expert Rev Hematol. 2019;12:195–205. https://doi.org/10.1080/17474086.2019.1585238.

    Article  CAS  PubMed  Google Scholar 

  20. Yanez L, Alarcon A, Sanchez-Escamilla M, Perales MA. How I treat adverse effects of CAR-T cell therapy. ESMO Open. 2020;4:e000746. https://doi.org/10.1136/esmoopen-2020-000746.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Penack O, Koenecke C Complications after CD19+ CAR T-Cell Therapy. Cancers (Basel). 2020; 12. e-pub ahead of print 20201119; https://doi.org/10.3390/cancers12113445.

  22. Yokohama A, Yokote K, Maruhashi T. Apheresis on aged patients/donors with complicated backgrounds like ischemic heart disease, arrhythmia, and others. Transfus Apher Sci. 2018;57:619–22. https://doi.org/10.1016/j.transci.2018.09.006.

    Article  PubMed  Google Scholar 

  23. Empringham B, Chiang KY, Krueger J. Collection of hematopoietic stem cells and immune effector cells in small children. Transfus Apher Sci. 2018;57:614–8. https://doi.org/10.1016/j.transci.2018.10.004.

    Article  PubMed  Google Scholar 

  24. Cid J, Carbasse G, Alba C, Perea D, Lozano M. Leukocytapheresis in nonmobilized donors for cellular therapy protocols: evaluation of factors affecting collection efficiency of cells. J Clin Apher. 2019;34:672–9. https://doi.org/10.1002/jca.21745.

    Article  PubMed  Google Scholar 

  25. Schulz M, Bialleck H, Thorausch K, Bug G, Dunzinger U, Seifried E, et al. Unstimulated leukapheresis in patients and donors: comparison of two apheresis systems. Transfusion. 2014;54:1622–9. https://doi.org/10.1111/trf.12506.

    Article  PubMed  Google Scholar 

  26. Stenzinger M, Bonig H. Risks of leukapheresis and how to manage them-A non-systematic review. Transfus Apher Sci. 2018;57:628–34. https://doi.org/10.1016/j.transci.2018.09.008.

    Article  PubMed  Google Scholar 

  27. Piñeyroa JA, Cid J, Lozano M. Get off on the right foot: how to plan an efficient leukocytapheresis to collect T cells for CAR T-cell manufacturing. Transfus Med Hemother. 2023; in press.

  28. Neyrinck MM, Vrielink H. Joint task force for E, certification. Calculations in apheresis. J Clin Apher. 2015;30:38–42. https://doi.org/10.1002/jca.21347.

    Article  PubMed  Google Scholar 

  29. Jo T, Yoshihara S, Hada A, Arai Y, Kitawaki T, Ikemoto J, et al. A clinically applicable prediction model to improve T cell collection in chimeric antigen receptor T cell therapy. Transpl Cell Ther. 2022;28:365.e361–7. https://doi.org/10.1016/j.jtct.2022.04.013.

    Article  CAS  Google Scholar 

  30. Allen ES, Stroncek DF, Ren J, Eder AF, West KA, Fry TJ, et al. Autologous lymphapheresis for the production of chimeric antigen receptor T cells. Transfusion. 2017;57:1133–41. https://doi.org/10.1111/trf.14003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. O’Reilly MA, Malhi A, Cheok KPL, Ings S, Balsa C, Keane H, et al. A novel predictive algorithm to personalize autologous T-cell harvest for chimeric antigen receptor T-cell manufacture. Cytotherapy. 2023;25:323–9. https://doi.org/10.1016/j.jcyt.2022.10.012.

    Article  CAS  PubMed  Google Scholar 

  32. O’Reilly M, Malhi A. Autologous CD3+ harvest prognostic model. In. https://cd3yield.shinyapps.io/cd3yield/, 2023.

  33. Jarisch A, Rettinger E, Sorensen J, Klingebiel T, Schafer R, Seifried E, et al. Unstimulated apheresis for chimeric antigen receptor manufacturing in pediatric/adolescent acute lymphoblastic leukemia patients. J Clin Apher. 2020;35:398–405. https://doi.org/10.1002/jca.21812.

    Article  PubMed  Google Scholar 

  34. Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfusion. Transfus Med Rev. 1988;2:76–94. https://doi.org/10.1016/s0887-7963(88)70035-8.

    Article  CAS  PubMed  Google Scholar 

  35. Bolan CD, Cecco SA, Wesley RA, Horne M, Yau YY, Remaley AT, et al. Controlled study of citrate effects and response to i.v. calcium administration during allogeneic peripheral blood progenitor cell donation. Transfusion. 2002;42:935–46. https://doi.org/10.1046/j.1537-2995.2002.00151.x.

    Article  CAS  PubMed  Google Scholar 

  36. Accorsi P, Dell’Isola M, Bonfini T, Giancola R, Spadano A, Fioritoni G, et al. Large volume leukapheresis with AMICUS cell separator in peripheral blood stem cell autologous transplant. Transfus Apher Sci. 2001;24:79–83. https://doi.org/10.1016/s0955-3886(00)00130-2.

    Article  CAS  PubMed  Google Scholar 

  37. Moog R. Harvesting of CD34 antigen-expressing cells with a new programme for the collection of mononuclear cells with use of the Amicus (Baxter) blood cell separator. Transfus Med. 2002;12:367–72. https://doi.org/10.1046/j.1365-3148.2002.00405.x.

    Article  CAS  PubMed  Google Scholar 

  38. Steininger PA, Strasser EF, Weiss D, Achenbach S, Zimmermann R, Eckstein R. First comparative evaluation of a new leukapheresis technology in non-cytokine-stimulated donors. Vox Sang. 2014;106:248–55. https://doi.org/10.1111/vox.12102.

    Article  CAS  PubMed  Google Scholar 

  39. Cancelas JA, Scott EP, Bill JR. Continuous CD34+ cell collection by a new device is safe and more efficient than by a standard collection procedure: results of a two-center, crossover, randomized trial. Transfusion. 2016;56:2824–32. https://doi.org/10.1111/trf.13769.

    Article  CAS  PubMed  Google Scholar 

  40. Harrer DC, Heidenreich M, Fante MA, Muller V, Haehnel V, Offner R, et al. Apheresis for chimeric antigen receptor T-cell production in adult lymphoma patients. Transfusion. 2022;62:1602–11. https://doi.org/10.1111/trf.17030.

    Article  CAS  PubMed  Google Scholar 

  41. Brauninger S, Bialleck H, Thorausch K, Seifried E, Bonig H. Mobilized allogeneic peripheral stem/progenitor cell apheresis with Spectra Optia v.5.0, a novel, automatic interface-controlled apheresis system: results from the first feasibility trial. Vox Sang. 2011;101:237–46. https://doi.org/10.1111/j.1423-0410.2011.01484.x.

    Article  CAS  PubMed  Google Scholar 

  42. Ali S, Chiang KY, Even-Or E, Di Mola M, Schechter T, Ali M, et al. Comparison between intermittent and continuous leukapheresis protocols for autologous hematopoietic stem cell collections in children. J Clin Apher. 2019;34:646–55. https://doi.org/10.1002/jca.21741.

    Article  PubMed  Google Scholar 

  43. Directive 2002/98/EC of the European Parliament and of the Council. In: Official Journal of the European Union L33 F, pp. 30–40, (ed). https://eur-lex.europa.eu/legal-content/EN/LSU/?uri=CELEX:32002L0098, 2003. p. 10.

  44. Ashford P, Allman S, Larsson S, Loper K, Moniz K, Sims-Poston L, et al. Standardization of cellular therapy terminology, coding and labeling: a review. Cytotherapy. 2022;24:577–82. https://doi.org/10.1016/j.jcyt.2022.02.009.

    Article  CAS  PubMed  Google Scholar 

  45. In: Aljurf M, Snowden JA, Hayden P, Orchard KH, McGrath E (eds). Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy: The JACIE Guide: Cham (CH), 2021.

Download references

Acknowledgements

We thank Sofie Terwel and Yolanda Cabrerizo for organizing regular virtual meetings of the Apheresis Working Group of the GoCart project and supporting us with written summaries of these meetings.

Author information

Authors and Affiliations

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

    Nina Worel

  2. Regional Blood Transfusion Service, Swiss Red Cross, Basel, Switzerland

    Andreas Holbro

  3. Division of Hematology, University Hospital Basel and University Basel, Basel, Switzerland

    Andreas Holbro

  4. Innovation Focus Cell Therapies, University Hospital Basel, Basel, Switzerland

    Andreas Holbro

  5. Department for Transfusion Medicine, Sanquin Blood Supply, Amsterdam, The Netherlands

    Hans Vrielink & Kaatje Le Poole

  6. Department of Hematology, Leiden University Medical Centre, Leiden, The Netherlands

    Claudia Ootjers & Ingrid Beer-Wekking

  7. EBMT Executive Office, Barcelona, Spain

    Tuula Rintala

  8. Apheresis and Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, University Clinic Hospital, IDIBAPS, University of Barcelona, Barcelona, Spain

    Miquel Lozano

  9. Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt a.M., Germany

    Halvard Bonig

  10. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    Halvard Bonig

Authors
  1. Nina Worel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Holbro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Ootjers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kaatje Le Poole
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ingrid Beer-Wekking
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tuula Rintala
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miquel Lozano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Halvard Bonig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NW and HB were responsible for writing the report, creating the figure and table, and reviewing and revising the report. AH, HV, CO, KLP, IBW, TR, and ML were responsible for writing, reviewing and revising the report.

Corresponding author

Correspondence to Nina Worel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

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

Worel, N., Holbro, A., Vrielink, H. et al. A guide to the collection of T-cells by apheresis for ATMP manufacturing—recommendations of the GoCART coalition apheresis working group. Bone Marrow Transplant 58, 742–748 (2023). https://doi.org/10.1038/s41409-023-01957-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-023-01957-x

Search

Advanced search

Quick links