TY - JOUR
T1 - Manufacturing mesenchymal stromal cells for the treatment of graft-versus-host disease
T2 - a survey amongst centers affiliated to the European Group of Blood and Marrow Transplantation
AU - Trento, Cristina
AU - Bernardo, Maria Ester
AU - Nagler, Arnon
AU - Kuçi, Selim
AU - Bornhäuser, Martin
AU - Köhl, Ulrike
AU - Strunk, Dirk
AU - Galleu, Antonio
AU - Sanchez-Guijo, Fermin
AU - Gaipa, Giuseppe
AU - Introna, Martino
AU - Bukauskas, Adomas
AU - Le Blanc, Katarina
AU - Apperley, Jane
AU - Roelofs, Helene
AU - Van Campenhout, Ann
AU - Beguin, Yves
AU - Kuball, Jürgen
AU - Lazzari, Lorenza
AU - Avanzini, Maria Antonietta
AU - Fibbe, Willem
AU - Chabannon, Christian
AU - Bonini, Chiara
AU - Dazzi, Francesco
N1 - Funding Information:
Financial disclosure: Supported by grants from the Bloodwise specialist programme 14019 and Bloodwise specialist programme 12006 (to F.D.); Bloodwise Clinical Research Training Fellowship 15029 (to A.G.); Italian Association for Cancer Research-AIRC and Italian Ministry of University and Research-MIUR (to C.B.); KWF grant UU 2015-7601 (to J.K.);, Ricerca Corrente no. 80380 (to M.A.A.).
Funding Information:
The authors thank all members of the Cell Therapy & Immunobiology Working Party of the EBMT., Financial disclosure: Supported by grants from the Bloodwise specialist programme 14019 and Bloodwise specialist programme 12006 (to F.D.); Bloodwise Clinical Research Training Fellowship 15029 (to A.G.); Italian Association for Cancer Research-AIRC and Italian Ministry of University and Research-MIUR (to C.B.); KWF grant UU 2015-7601 (to J.K.);, Ricerca Corrente no. 80380 (to M.A.A.)., Conflict of interest statement: C.B. received research support from Molmed s.p.a and Intellia Therapeutics and received the fee for the participation to an advisory Board by GSK. The other authors disclose no potential conflicts of interest., Authorship statement: C.T. and M.E.B. contributed equally to this study.
Publisher Copyright:
© 2018
PY - 2018/11/24
Y1 - 2018/11/24
N2 - BACKGROUND: The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease (GvHD) 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 amongst different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting amongst different centers. In order to acquire information on MSC manufacturing we have sent a questionnaire to the European Group for Blood and Marrow Transplantation (EBMT) centers registered as producing MSC.METHODS: Data from 17 centers were obtained and analyzed by means of a two-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex-vivo expansion, data on MSC product specification for clinical release.RESULTS: The majority of centers manufactured MSC from bone marrow (88%), whilst only two 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 one center manufactured exclusively autologous MSC. The large majority (71%) of these facilities 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.DISCUSSION: 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.
AB - BACKGROUND: The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease (GvHD) 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 amongst different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting amongst different centers. In order to acquire information on MSC manufacturing we have sent a questionnaire to the European Group for Blood and Marrow Transplantation (EBMT) centers registered as producing MSC.METHODS: Data from 17 centers were obtained and analyzed by means of a two-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex-vivo expansion, data on MSC product specification for clinical release.RESULTS: The majority of centers manufactured MSC from bone marrow (88%), whilst only two 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 one center manufactured exclusively autologous MSC. The large majority (71%) of these facilities 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.DISCUSSION: 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.
KW - Cellular therapy
KW - Graft-versus-host disease
KW - Manufacturing
KW - Mesenchymal stromal cells
KW - Product specification
KW - Release criteria
UR - http://www.scopus.com/inward/record.url?scp=85051647507&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.07.015
DO - 10.1016/j.bbmt.2018.07.015
M3 - Article
C2 - 30031938
SN - 1083-8791
VL - 24
SP - 2365
EP - 2370
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 11
ER -