Development of a potency assay to evaluate immunomodulatory properties of human autologous liver-derived progenitor cells (HALPC) for the treatment of acute on chronic liver failure

Background & Aim HepaStem is composed of human autologous liver-derived progenitor cells (HALPC) manufactured under GMP conditions and developed by Promethera Biosciences for the treatment of fibro-inflammatory disorders such as acute-on-chronic liver failure (ACLF). ACLF is a life-threatening complication of cirrhosis characterized by an acute liver decompensation associated with multiple organ failure and a very low survival rate. ACLF is linked to multiple cell type dysfunction, immunological imbalance and increased local (liver) and systemic inflammation. Preclinical data demonstrated that HepaStem has immunomodulatory properties. It is expected that HepaStem exerts immunomodulatory effects by interactions with immune cells of the patient and by paracrine effects through the various factors they secrete. It is expected that HepaStem will play a favorable role in treating the immunological disturbances observed in patients with ACLF and ultimately will be able to restore liver homeostasis. Methods, Results & Conclusion After a phase IIa clinical trial showing that IV administration of HepaStem was safe in ACLF patients, Promethera Biosciences initiated beginning of 2020 an efficacy study across multiple centres in Europe. In this context, the strategy followed by Promethera to develop the potency assay for release testing of batches that will be used in clinical trial is based on the immunomodulatory properties as main mechanism of action targeted for this pathology with (1) the development of an in vitro cell-based-assay that directly measures a biological activity of HepaStem representative of the biological effect expected in clinics and (2) then the development of non-biological analytical assay(s) used as surrogate markers to allow robust and easy routine evaluation of the potency. After identification of several well described soluble mediators with immunomodulatory properties, loss- and gain- of function experiments were performed to identify PGE2 as the main mediator associated with the suppression of APC-induced CD4+ T cell proliferation as well as inhibition of pro-inflammatory cytokine secretion such as TNFa. A very good correlation between the concentration of PGE2 in HepaStem conditioned medium after pro-inflammatory stimulation and the ability to inhibit APC-induced CD4+ T cell proliferation in vitro allowed together with the method validation to determine a first specification for the potency assay that will be later refined based on clinical data.