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

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.

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…The number of MSC infusions as well as the MSC doses varied greatly across the trials. Trento et al [38] analyzed data from 17 European Group for Blood and Marrow Transplantation (EBMT) centers via questionnaire, especially focused on MSC manufacturing. Eighty-eight percent of centers manufactured bone marrow-derived MSCs, while only 2 centers produced from umbilical cord.…”

Mesenchymal stromal cells for acute graft‐versus‐host disease: response at 1 week predicts probability of survival

“…This observation is supported by the findings of other groups (Le Blanc et al , ; Kebriaei et al , ; von Dalowski et al , ), whereby when MSCs from the same donor were used to treat several patients, only a proportion of them achieved remission. Such a perspective suggests that the variability in MSC manufacturing bears a limited impact (Trento et al , ). Overall, these findings provide an innovative angle that could be harnessed to improve the complex design of future clinical studies for the treatment of GvHD with MSCs.…”

A double‐virally‐inactivated (Intercept–solvent/detergent) human platelet lysate for in vitro expansion of human mesenchymal stromal cells

“…As HPL is increasingly used for ex vivo propagation of stromal cell based medicinal products, the blood transfusion and manufacturers communities need to address a number of issues, including how to ensure HPL standardization and pathogen safety . The pooling of approximately 50 to 250 PC donations appears needed to provide batch‐to‐batch consistency but statistically increases the risk of virus contamination .…”