Paracetamol overdose is the leading cause of acute liver failure in the Western world, and the only drug that works must be given within about eight hours—after that, patients have no treatment option except a liver transplant, which is scarce, expensive, and risky. This project aims to change that by testing an off-the-shelf cell therapy: immune cells called macrophages, taken from universal blood group O donors, frozen, stored at the hospital, and thawed for infusion when needed. In mouse studies, these alternatively-activated macrophages reduce liver cell death and inflammation while boosting repair. The team has already shown the approach is safe in chronic liver disease and in a small trial for paracetamol toxicity. If the phase 1 trial succeeds, it would open the door to a larger randomised trial—not just for paracetamol overdose, but for other causes of acute liver failure where no specific treatment exists. That could reduce the number of patients needing emergency transplants, easing pressure on transplant waiting lists and cutting healthcare costs.
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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.
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