Macrophage Therapy for Acute Liver Failure

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Need: Acute liver failure (ALF) has no effective treatment other than liver transplantation, which has limited use because of its associated morbidity/mortality, expense to the health provider and the scarcity of donor livers. Paracetamol(acetaminophen) overdose is the commonest cause in the Western world. The only treatment for paracetamol overdose is acetylcysteine, which is preventative with regard to ALF only if treatment starts soon after overdose (within around 8h). For other causes of ALF there is currently no specific treatments. Solution: The proposed product is an off-the-shelf, allogeneic, alternatively-activated, macrophage cell therapy derived from 'universal' blood group O donor monocytes requiring no further matching of donor to recipient. The product will be frozen, stored close to the point of treatment and thawed on demand prior to infusion.Rationale: Alternatively-activated macrophages reduce liver necrosis and inflammatory cytokines, and increase proliferating hepatic progenitors in mouse models of ALF. Our solution is anchored by these world-leading pre-clinical studies, success in delivering macrophage therapy to patients with chronic liver disease (MATCH Trial, supported by DPFS, Moroni et al. Nature Medicine 2019) and the recent completion of the first phase 1 trial in paracetamol toxicity (Lancet EBioMedicine 2019 https://www.ebiomedicine.com/article/S2352).Development plan: In the first 18 months we will complete the IMPD and obtain a clinical trial authorisation. This process will be guided by the Cell and Gene Therapy Catapult and builds on our previous success with CTA applications for macrophage cell therapy in liver disease. In the following 30 months will deliver a phase 1 clinical trial of allogeneic, alternatively activated, macrophages in a phase 1 clinical trial in patients with paracetamol-induced acute liver injury. This builds on the unique local expertise in clinical trials of macrophage cell therapy in chronic liver disease and phase 1 clinical trials in acute paracetamol overdose.If successful this study paves the way for a randomised controlled trial of macrophage cell therapy for this condition and importantly will facilitate the development of macrophage cell therapy for other causes of acute liver failure.