Background

Application of mesenchymal stromal cells (MSCs) as advanced therapy medicinal product (ATMP) is very versatile due to their regenerative and immunomodulatory properties. Approximately 90 therapeutic doses have been produced for 9 phase 1 - 3 non-commercial clinical trials at IKT Ulm. Autologous non-cryopreserved MSC were used within 24 after production for bone augmentation, treatment of fractures, osteonecrosis, osteoarthritis and multiple sclerosis.

Methods

MSC used in 9 clinical trials are manufactured in a xenogenic free system established at 5 different manufacturing centers in Europe. Heparinized bone marrow (BM) is received within 24 hours and seeded in alphaMEM supplemented with platelet lysate (50.000/cm2). Medium exchange is performed 2x per week for 10 or 14 days and harvested MSC (MSCP0) are reseeded at a density of 4000 cells/cm2 for 5 or 7 days. The investigational medicinal product (IMP) is packaged in syringes in physiological saline supplemented with or without 5% human serum albumin and immediately shipped after release to be applied to the patient within 24 hours or 48 hours using an accompanied transport service of a qualified courier company.

Results

All trials have proven the feasibility and safety of MSC so far. There were no adverse events. Consolidation after one year was >90% in ORTHO1 trial (non-union bone fractures), >70% in ORTHO2 trial (osteonecrosis of femoral head) and 100% in MAXILLO1 trial (bone augmentation prior to dental implant)

The use of autologous, non-cryopreserved MSC may be critical. Due to yet unknown factors, failure of manufacturing clinical doses occurred for some patients. Factors that may influence the manufacturing process are e.g. transport time, experience of the physician performing the small volume BM collection, but also patient variation and costs for manufacturing autologous MSC for individual therapy are very high.

Conclusion

The use of autologous MSC is safe, effective but expensive. Failure of MSC manufacturing cannot be excluded. Cost reduction could be performed by using automated, large scale bioreactor systems for manufacturing of huge amounts of cells from one or few donors for allogeneic applications. A product from the shelf could be transported frozen, without the request for an accompanied transport. We have tested different bioreactor systems for their suitability to isolate and/or expand MSC.

Offenlegung Interessenkonflikt:

The authors declare no commercial, proprietary or financial interest. The manufacturing of MSC and the clinical trials were financed by projects within the European Union"s Seventh Framework Programme and the European Union"s Network HORIZON2020. The materials presented and views expressed here are the responsibility of the authors only. The European Union Commission takes no responsibility for any use made of the information set out.