The scientific challenge:
Mesenchymal stromal cells (MSC) are currently undergoing clinical testing in a variety of clinical conditions aiming at repair through direct or indirect mechanisms. Their ability to form bone or cartilage is used to directly repair bone or cartilage defects. In other conditions their therapeutic effects are based on their anti-inflammatory and immune-modulatory properties. The regenerative properties of MSC in the RETHRIM project is focused on the latter.
Immune mediated tissue injury represents the principle mechanism underlying a variety of autoimmune disorders, including Crohn’s disease and Multiple Sclerosis. Similar forms of tissue injury can be observed in disorders that are due to alloimmune responses, including solid organ graft rejection and Graft-versus-Host Disease (GvHD) after allogeneic stem cell transplantation. Acute GvHD represents an inflammatory disorder that suppresses regenerative responses in the body, sometimes resulting in permanent damage of the affected tissues i.e. gut, liver, lung and skin. By producing soluble factors and by inducing regulatory mechanisms and anti-inflammatory cells, MSC may revert this process. The production of anti-inflammatory mediators capable of stimulating the recovery of injured tissue plays an important role in this process. The precise immune modulatory mechanisms of MSC are not entirely clear. The picture below shows an overview of the possible mechanisms involved.
The clinical challenge:
For many hematological malignant disorders, allogeneic Stem Cell Transplantation (SCT) represents the only potentially curative form of treatment. The curative potential of allo-SCT relies on a potent and critical graft-versus-tumor effect. At the same time, acute graft-versus-host disease remains a major cause of non-relapse mortality, since there are no effective strategies to separate graft-versus-tumor from graft-versus-host effects. The incidence of GvHD following SCT ranges from 10-80% dependent upon the risk factors present. First line treatment consists of immuno-suppressive therapy with corticosteroids. Approximately 50% of patients suffering from acute GvHD improve following corticosteroid treatment, while 50% of patients will develop steroid-refractory aGvHD, which has a high mortality rate (75%) and surviving patients often develop chronic GvHD, which reduces life expectancy and performance.
In the past several years the regenerative potential of MSC has been evaluated in clinical trials. Their use in GvHD has been most closely studied. The successful treatment of severe steroid refractory grade IV aGvHD of the gut and liver in a 9-year-old using MSC over 10 years ago, was the initiator of a large number of phase I and II clinical trials using MSC to threat GvHD. The results from trials conducted by the consortium members indicate that the use of third-party Mesenchymal Stromal Cells (MSC) might be an effective therapy for visceral GvHD. However, no definitive proof of effectiveness through double-blind placebo controlled multicentre studies has been obtained. The current phase III clinical trial is aimed at setting a new standard for the treatment of visceral GvHD. MSC regenerative therapy will be employed to determine its potential to improve the rates of remission and overall survival and to improve quality of life.