Birgit Sawitzki1, Paul N Harden2, Petra Reinke3, Aurélie Moreau4, James A Hutchinson5, David S Game6, Qizhi Tang7, Eva C Guinan8, Manuela Battaglia9, William J Burlingham10, Ian S D Roberts11, Mathias Streitz12, Régis Josien13, Carsten A Böger14, Cristiano Scottà15, James F Markmann16, Joanna L Hester17, Karsten Juerchott18, Cecile Braudeau13, Ben James19, Laura Contreras-Ruiz20, Jeroen B van der Net2, Tobias Bergler14, Rossana Caldara21, William Petchey2, Matthias Edinger22, Nathalie Dupas23, Michael Kapinsky24, Ingrid Mutzbauer19, Natalie M Otto3, Robert Öllinger25, Maria P Hernandez-Fuentes15, Fadi Issa17, Norbert Ahrens26, Christoph Meyenberg27, Sandra Karitzky28, Ulrich Kunzendorf29, Stuart J Knechtle30, Josep Grinyó31, Peter J Morris32, Leslie Brent33, Andrew Bushell17, Laurence A Turka16, Jeffrey A Bluestone34, Robert I Lechler15, Hans J Schlitt5, Maria C Cuturi4, Stephan Schlickeiser12, Peter J Friend35, Tewfik Miloud23, Alexander Scheffold36, Antonio Secchi37, Kerry Crisalli16, Sang-Mo Kang7, Rachel Hilton6, Bernhard Banas14, Gilles Blancho4, Hans-Dieter Volk12, Giovanna Lombardi15, Kathryn J Wood17, Edward K Geissler38. 1. Institute of Medical Immunology, Charité, Universitätsmedizin Berlin, Berlin, Germany. 2. Oxford Transplantation Centre, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK. 3. BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany. 4. Centre de Recherche en Transplantation et Immunologie, Nantes Université, Inserm, Nantes, France; Institute of Transplantation Urology Nephrology, Nantes, France. 5. Department of Surgery, University of Regensburg, University Hospital Regensburg, Regensburg, Germany. 6. Guy's & St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK. 7. Division of Transplantation, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA. 8. Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston MA, USA. 9. Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy. 10. Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. 11. Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 12. Institute of Medical Immunology, Charité, Universitätsmedizin Berlin, Berlin, Germany; BIH Center for Regenerative Therapies, Charité and Berlin Institute of Health, Charité, Universitätsmedizin Berlin, Berlin, Germany. 13. Centre de Recherche en Transplantation et Immunologie, Nantes Université, Inserm, Nantes, France; Institute of Transplantation Urology Nephrology, Nantes, France; Laboratoire d'Immunologie, Cimna, Centre Hospitalier Universitaire, Nantes, France. 14. Department of Nephrology, University of Regensburg, University Hospital Regensburg, Regensburg, Germany. 15. MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK. 16. Center for Transplantation Sciences, Mass General Hospital, Boston, MA, USA. 17. Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. 18. BIH Center for Regenerative Therapies, Charité and Berlin Institute of Health, Charité, Universitätsmedizin Berlin, Berlin, Germany. 19. Department of Surgery, University of Regensburg, University Hospital Regensburg, Regensburg, Germany; Division of Personalized Tumor Therapy, Fraunhofer Institute for Experimental Medicine and Toxicology, Regensburg, Germany. 20. Department of Experimental Medicine, DFCI, Boston, MA, USA. 21. Transplant Medicine, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy. 22. Department of Internal Medicine III, University of Regensburg, University Hospital Regensburg, Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany. 23. Beckman Coulter Life Sciences, Immunotech, Marseille, France. 24. Beckman Coulter, Krefeld, Germany. 25. Department of Surgery, Charité Campus Mitte, Campus Virchow Klinikum, Charité Universitätsmedizin, Berlin, Germany. 26. Institute for Clinical Chemistry and Laboratory Medicine, Transfusion Medicine, University of Regensburg, University Hospital Regensburg, Regensburg, Germany. 27. KOEHLER eClinical, Freiburg, Germany. 28. Miltenyi Biotec, Bergisch Gladbach, Germany. 29. Clinic for Nephrology and Hypertension, Christian Albrechts University, University Clinic Schleswig-Holstein, Kiel, Germany. 30. Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA. 31. Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain. 32. Centre for Evidence in Transplantation, Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. 33. St Mary's Hospital Transplant Unit, Paddington, London, UK. 34. UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. 35. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. 36. Institute for Immunology, Christian Albrechts University, University Clinic Schleswig-Holstein, Kiel, Germany. 37. Vita-Salute San Raffaele University Milan, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy. 38. Department of Surgery, University of Regensburg, University Hospital Regensburg, Regensburg, Germany; Division of Personalized Tumor Therapy, Fraunhofer Institute for Experimental Medicine and Toxicology, Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany. Electronic address: edward.geissler@klinik.uni-regensburg.de.
Abstract
BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.
BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.
Authors: Henrik Ekberg; Helio Tedesco-Silva; Alper Demirbas; Stefan Vítko; Björn Nashan; Alp Gürkan; Raimund Margreiter; Christian Hugo; Josep M Grinyó; Ulrich Frei; Yves Vanrenterghem; Pierre Daloze; Philip F Halloran Journal: N Engl J Med Date: 2007-12-20 Impact factor: 91.245
Authors: Anders H Kverneland; Mathias Streitz; Edward Geissler; James Hutchinson; Katrin Vogt; David Boës; Nadja Niemann; Anders Elm Pedersen; Stephan Schlickeiser; Birgit Sawitzki Journal: Cytometry A Date: 2016-05-03 Impact factor: 4.355
Authors: T P P van den Bosch; L B Hilbrands; R Kraaijeveld; N H R Litjens; F Rezaee; D Nieboer; E W Steyerberg; J A van Gestel; D L Roelen; M C Clahsen-van Groningen; C C Baan; A T Rowshani Journal: Am J Transplant Date: 2017-04-22 Impact factor: 8.086
Authors: James A Hutchinson; Paloma Riquelme; Beate G Brem-Exner; Maren Schulze; Martina Matthäi; Lutz Renders; Ulrich Kunzendorf; Edward K Geissler; Fred Fändrich Journal: Transpl Int Date: 2008-07-10 Impact factor: 3.782
Authors: A L Putnam; N Safinia; A Medvec; M Laszkowska; M Wray; M A Mintz; E Trotta; G L Szot; W Liu; A Lares; K Lee; A Laing; R I Lechler; J L Riley; J A Bluestone; G Lombardi; Q Tang Journal: Am J Transplant Date: 2013-09-18 Impact factor: 8.086
Authors: Elly J F Vereyken; Marina D Kraaij; Carla C Baan; Farhad Rezaee; Willem Weimar; Kathryn J Wood; Pieter J M Leenen; Ajda T Rowshani Journal: PLoS One Date: 2013-07-29 Impact factor: 3.240
Authors: Marie B Nielsen; Kristian Ravlo; Marco Eijken; Nicoline V Krogstrup; Morten Bue Svendsen; Chadi Abdel-Halim; Mikkel Steen Petersen; Henrik Birn; Mihai Oltean; Bente Jespersen; Bjarne K Møller Journal: Clin Exp Immunol Date: 2021-09-29 Impact factor: 4.330
Authors: Katsuyoshi Shimozawa; Laura Contreras-Ruiz; Sofia Sousa; Ruan Zhang; Urvashi Bhatia; Kerry C Crisalli; Lisa L Brennan; Laurence A Turka; James F Markmann; Eva C Guinan Journal: Am J Transplant Date: 2021-09-27 Impact factor: 9.369
Authors: Erika M J Siren; Haiming D Luo; Franklin Tam; Ashani Montgomery; Winnie Enns; Haisle Moon; Lyann Sim; Kevin Rey; Qiunong Guan; Jiao-Jing Wang; Christine M Wardell; Mahdis Monajemi; Majid Mojibian; Megan K Levings; Zheng J Zhang; Caigan Du; Stephen G Withers; Jonathan C Choy; Jayachandran N Kizhakkedathu Journal: Nat Biomed Eng Date: 2021-08-09 Impact factor: 25.671