Abstract
BackgroundMesenchymal stromal cells (MSC) are largely investigated in clinical trials aiming to control inappropriate immune reactions (GVHD, Crohn’s disease, solid organ transplantation). As the percentage of MSC precursors in bone marrow is very low, these must be expanded in vitro to obtain therapeutic cell doses. We describe here the constitution of an allogeneic human third-party MSC bank from screened healthy volunteer donors in compliance with quality specifications and ISCT-release criteria and report follow-up of different aspects of this activity since 2007.Methods68 clinical-grade large-scale MSC cultures were completed and analyzed. The whole process was described, including volunteer donor screening, bone marrow collection, mononuclear cell isolation and expansion over 4 weeks, harvesting, cryopreservation, release, administration and quality controls of the cells (including microbiology, phenotype, and potency assays).ResultsFrom 59 validated donors, 68 cultures were completed (mean of final yields: 886 × 106 cells/culture) and a total of 464 MSC aliquots have been produced and stored in liquid nitrogen (mean of 132.8 × 106 cells/bag). Each MSC batch underwent extensive testing to verify its conformity with EBMT and ISCT release criteria and was individually validated. As of June 1 2015, 314 bags have been released and infused to patients included in 6 different clinical protocols. All thawed MSC units satisfied to release criteria and no infusion-related toxicity was reported.ConclusionIn conclusion, despite low passage cultures, we have been able to create an allogeneic “off-the-shelf” MSC bank with a large number of frozen aliquots and report here an efficient clinical-grade MSC banking activity in place for more than 7 years. Our challenge now is to produce MSC in compliance with good manufacturing practices (GMP) as, in the meantime, MSC have become considered as advanced therapy medicinal products (ATMP). Another significant challenge remains the development of relevant potency assay.
Highlights
Mesenchymal stromal cells (MSC) are largely investigated in clinical trials aiming to control inappropriate immune reactions (GVHD, Crohn’s disease, solid organ transplantation)
In the Laboratory of Cell and Gene Therapy (LTCG, CHU of Liège), we started in late 2006 a “MSC bank” based on clinical-grade expansion of MSC from bone marrow (BM) samples obtained from healthy volunteer donors
Large‐scale cultures—process validation After a few small-scale MSC expansions to set up the process, three large-scale clinical MSC cultures were initiated for validation with three different bone marrow (BM) samples obtained from healthy volunteer donors
Summary
Mesenchymal stromal cells (MSC) are largely investigated in clinical trials aiming to control inappropriate immune reactions (GVHD, Crohn’s disease, solid organ transplantation). The International Society for Cellular Therapy (ISCT) has established the minimum criteria to define MSC and described them as a heterogeneous population of Lechanteur et al J Transl Med (2016) 14:145 spindle-shaped, plastic-adherent cells isolated from bone marrow, adipose tissue, and many other tissue sources such as umbilical cord or cord blood. They must express certain cell surface markers (CD73, CD90, CD105) and lack expression of others (CD45, CD34, CD14, HLA-DR) and have the capacity to differentiate into osteoblasts, adipocytes and chondroblasts when cultured in particular in vitro conditions [10, 11]. Cell processing facilities have established procedures for large scale production of MSC
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