Scaling-up GMP production of human umbilical-cord mesenchymal stromal cells for CoViD19 patients experiencing moderate to severe Acute Respiratory Distress Syndrome – MSCoViD

The SARS-CoV-2 identified in China in January 2020 is the cause of an unprecedented pandemic. Although mostly asymptomatic, in 20% of cases CoViD-19 will lead to severe forms, characterized by a cytokine storm, major pulmonary inflammation, degradation of alveolar epithelial cells and capillary endothelial cells, resulting in acute respiratory distress syndrome (ARDS) which may lead to the patient’s death in about 20 to 50% of cases.
According to the pre-clinical experience of two of the partners of the MSCoViD project (Unité de Thérapie Cellulaire et banque de Tissus, CHU, Nancy et Ingénierie Moléculaire et Physiopathologie Articulaire, UMR CNRS, Nancy), administration of thawed umbilical cord mesenchymal stromal cells (UC-MSCs) in murine and porcine sepsis models resulted in a significant improvement in lung failure due to their strong immunomodulatory properties. To date, it has been reported that in 8/8 patients with CoViD19, clinical signs, particularly pulmonary ones, have considerably improved or disappeared after infusion of UC-MSCs. Based on his pre-clinical and clinical experience, partner 1 proposed a clinical trial, relying on repeated infusions of UC-MSCs during moderate to severe ARDS associated with SARS-Cov-2. This is a phase IIa comparative efficacy study with 30 patients which has just been authorized by the French regulatory agency, ANSM.
Thus, the need to produce large amount of UC-MSCs in a short time to allow the development of efficacy clinical trials including a significant number of patients who receive repeated infusions has highlighted the importance of scaling-up the production in academic production platforms. The third partner of the project (Reactions and Process Engineering Laboratory, UMR CNRS, Nancy) has been working for a long time on the culture of UC-MSCs in stirred tank bioreactors with microcarriers and has developed on-line quality control techniques. In particular, an optimization of the expansion process was carried out by defining the microcarriers (adhesion supports), the culture modes and the stirring strategies best suited to the specificities of these cells.
In this collaborative translational project, we wish to rely on the complementary and multidisciplinary expertise (cell therapy, biology of MSCs, bioprocess engineering) of each of the partners to scale up and intensify the GMP production of UC-MSCs in order to conduct efficacy clinical trials for the treatment of patients with CoViD19 and presenting an ARDS. To achieve this goal, cultures at a 3 L scale will be initiated using a commercial bioreactor, based on the culture process already developed in research grade. Four batches (including 3 clinical grade batches) of 2 to 3 billion cells each will be produced in a bioreactor, on microcarriers. Cell production will then be compared with those produced in 2 D-culture in multi-layered flasks, according to the technique authorized in current clinical protocols and derived from the same raw material. Comparability will be established on the basis of phenotypic and on-line metabolic quality controls (carried out online) but also functional, to verify the maintaining of the immunomodulatory properties sought in the indication of sepsis. The short-term perspectives of this project are the clinical transfer of UC-MSCs produced in stirred tank bioreactors for the treatment of ARDS related to CoViD19 but also, in the mid-term, for other indications using UC-MSCs.
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