GMP-manufactured, heterologous human adult-derived progenitor cell therapy for NASH-fibrosis
(2017) International Symposium of the IAP-VII network HEPRO “Liver disease and Regeneration” — Location: Leuven, Belgium
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- Abstract
- Human Adult Liver-derived Progenitor Cells (Hepastem) were reproducibly isolated, manufactured and cryopreserved in clinical grade conditions. A bedside cell product formulation protocol was validated, to create an off-the-shelf product, easy to apply, without the need of GMP laboratories near the patient. The safety and tolerability of their intraportal injection has been shown in a phase I/II trial in young patients with metabolic disorders (UCD and Crigler-Najjar). Thanks to their mesenchymal features, the cells also display immunomodulatory properties which makes them promising cell therapy candidates for the treatment of chronic liver diseases, like fibrosis caused by steatohepatitis. The proposed mechanism of action is a systemic hit-and-run suppression of inflammation and stellate cell activation (which causes collagen deposition) through the secretion of potent cytokines. Indeed, in vitro studies have shown a significant increase of anti-inflammatory and anti-fibrotic cytokines including HGF, IDO, and PGE2, upon their incubation with an inflammatory cocktail. Co-culture studies demonstrated that the anti-inflammatory response of those liver progenitor cell is mediated via the inhibition of both T-lymphocyte response in an MLR reaction and the generation of dendritic cells when induced and matured in vitro. In a preclinical established high-fat model, the potency of Hepastem was compared to a vehicle, either with or without immunosuppression (cyclosporine). While immunosuppression itself did not affect the disease progression in this model, Hepastem treatment (1, 2 or 3 intravenous injections of 12.5x106 cells/kg) significantly and dose-dependently decreased collagen deposition in the pericentral region, as revealed by Sirius Red staining. Interestingly, a single injection significantly decreased the NAS score, which was mainly attributed to reduction in inflammation, which confirms the proposed anti-inflammatory mechanism of action. Oil red O and glycogen contents were less obvious in the treated groups, independently of the use of immunosuppression. Altogether, these data reveal the anti-fibrosis and anti-NASH potential of Hepastem under immunosuppression regimen and support its clinical development for the treatment of late phase NASH patients showing fibrosis formation.
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Mazza, G., Gellynck, K., Rommelaere, G., Najimi, M., Lombard, C., Thonnard, J., Tchelingerian, J., & Sokal, E. (2017). GMP-manufactured, heterologous human adult-derived progenitor cell therapy for NASH-fibrosis. International Symposium of the IAP-VII network HEPRO “Liver disease and Regeneration”, Leuven, Belgium. https://hdl.handle.net/2078.5/79097