Human liver-derived cell therapy for Immuno-mediated and inflammatory liver diseases

Kris Gellynck, Giuseppe Mazza, Joelle Thonnard, Mustapha Najimi, Etienne Sokal

HepaStem is a human liver derived progenitor cell manufactured under  GMP conditions by Promethera Biosciences. A phase I/II clinical trial already showed the cell therapy was safe and well tolerated in 20 paediatric patients. The cell's metabolic properties were used to treat genetic diseases like urea cycle  disorder, but as HepaStem has similarities to mesenchymal stem cells, it also has immunomodulatory properties.

This immunomodulation will be now be applied in a clinical trial with patients suffering from acute-on-chronic-liver-failure (ACLF). They have a chronic liver fibrosis/cirrhosis,  but are admitted to the hospital with an acute liver decompensation on top of the cirrhosis.  ACLF is defined by an imbalance of the immune system, which progresses the diseases towards multiple organ failure. The survival of these ACLF patients drops below  50% in the first 3 months after hospital admission, but once ACLF progression is overturned, patients can return to a normal state, where the liver fibrosis is chronic only.  Rebalancing the immune system, involved a complex mix of immuno-cytokines and cells.

MSCs, and our liver progenitor cells are able to suppress T lymphocyte activation and proliferation, by soluble factors and cell-cell contact is not required for this inhibition to happen. Secreted cytokines like TGF-β, HGF, PGE2, IDO are involved in this mechanism. Apart from the T-lymphocytes, dendritic cells (DCs) play a key role in the induction of immunity and tolerance, depending on the activation and maturation stage.  MSCs have been demonstrated to interfere with DC differentiation, maturation and function, through Il-6 and M-CSF.

The abovementioned molecules are all cytokines that are well secreted by HepaStem, affirming its immunomodulatory properties.  Even more, MSCs and our HepaStem cells lack surface expression of costimulatory molecules, such as CD80 and CD86 ,and it is believed that MSCs can render T cells anergic. When a cocktail of inflammatory cytokines (IFN-ɣ, IL1b, TNF-α) is added to the in vitro culture of liver progenitor cells we can see that surface markers (CD54, CD274, ..) are increasing, thus the cells are adapting to the inflamed environment.  This adaptation is the difference between using a molecular drug substance and a cell therapy; Human MSCs cells like HepaStem can interact with the different environment that will be patient-specific.

HepaStem is liver derived and has shown to migrate towards the liver when infused in the peripheral vein, and a homing to inflamed body areas was observed; both helping the cells to migrate to the liver fibrotic areas that are the subject of this project.

Promethera is planning a clinical trial involving multiple centres spread over Europe, in which ACLF patients will receive 4 injections of HepaStem. Blood and tissue analysis will be evaluated to investigate the effect of the HepaStem modulation on the immune system and the ACLF progression of these patients.