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Biol Blood Marrow Transplant. 2018 Nov;24(11):2365-2370. doi: 10.1016/j.bbmt.2018.07.015. Epub 2018 Jul 20.

Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation.

Author information

1
School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom.
2
Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy.
3
Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Tel-Hashomer, Israel.
4
Division for Stem Cell Transplantation and Immunology, University Hospital for Children and Adolescents, Frankfurt am Main, Germany.
5
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany.
6
Institute of Clinical Immunology, University Leipzig, Leipzig, Germany; Fraunhofer Institute of Cellular Therapy and Immunology and Institute of Cellular Therapeutics, Hannover Medical School, Hannover, Germany.
7
Experimental & Clinical Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria.
8
Hematology Department, IBSAL-Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain.
9
Laboratorio di Terapia Cellulare e Genica Stefano Verri, ASST Monza, Monza, Italy.
10
USS Centro di Terapia Cellulare "G.Lanzani", ASST Ospedale Papa Giovanni XXIII, Bergamo, Italy.
11
Center of Hematology, Oncology and Transfusion Medicine, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania.
12
Department of Haematology, Karolinska University Hospital, Sweden, Stockholm.
13
Department of Haematology, Faculty of Medicine, Imperial College London, London, United Kingdom.
14
Leiden University Medical Centre, Leiden, The Netherlands.
15
Transplantation Laboratory Hematology, U.Z. Gasthuisberg, Leuven, Belgium.
16
Laboratory of Cell and Gene Therapy, Clinical Haematology, CHU of Liège, Liège, Belgium.
17
Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
18
Cell Factory GMP, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
19
Laboratorio Immunologia e dei Trapianti, Cell Factory, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
20
Institut Paoli Calmettes & Inserm CBT-1409, Centre d'Investigations Cliniques en Biothérapies, Marseille, France.
21
Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, University Vita-Salute San Raffaele and Ospedale San Raffaele Scientific Institute, Milan, Italy.
22
School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom. Electronic address: francesco.dazzi@kcl.ac.uk.

Abstract

The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.

KEYWORDS:

Cellular therapy; Graft-versus-host disease; Manufacturing; Mesenchymal stromal cells; Product specification; Release criteria

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