Macrophage Therapy for Acute Liver Failure

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.

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).

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 and published in Nature Medicine) and the recent completion of the first phase 1 trial in paracetamol toxicity (Lancet EBioMedicine 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 patients with paracetamol-induced acute liver injury (using continual reassessment method). This builds on the local expertise in clinical trials of macrophage cell therapy in chronic liver disease and phase 1 clinical trials in acute paracetamol overdose.

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. In the Western world paracetamol (acetaminophen) overdose (POD) is the commonest cause of ALF. It is estimated there are at least 1000 POD-ALF cases treated in liver transplant centres in the US and EU (mostly UK) each year. Mortality in this group is around 30-35%, with about 30% receiving a liver transport (most of whom survive). Many of these patients occupy critical care beds for weeks. The only treatment for paracetamol overdose is acetylcysteine, which is only effective if started soon after overdose (within 8h). 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. These properties will minimize manufacturing costs and allow widespread health service adoption if clinically- and cost-effective. Alternatively-activated macrophages reduce liver necrosis and inflammatory cytokines, and increase regeneration in mouse models of ALF.

Advantages of using alternatively-activated macrophages are:
1. Our pre-clinical model of paracetamol toxicity is a faithful representation of human disease. In this model our solution has clear efficacy even when delivered after liver injury is well-established (unlike established antidote NAC, and new drug calmangafodipir). This is because this cellular therapy reverses injury rather than preventing it.
2. Macrophages are biologically well-defined, can be isolated and then differentiated in large numbers from blood monocytes. This established pipeline for producing clinical grade macrophages is scalable and cost-effective.
3. Macrophages have been shown to be stimulate liver regeneration, and be anti-inflammatory in multiple mouse models of liver injury and, critically, and are safe in human studies.
4. Macrophages are terminally differentiated with limited lifespan thus increasing safety.

If this study was successful and passed the milestones described then we would be in a position to then perform a multi-center phase 2 randomised controlled study. Collectively, Forbes, Dear, Campbell and Weir have a track record of taking first in human cell therapies to the clinic, and and performing studies in this patient group. The Clinical Research Facility, has phase 1/2 experience to deliver this potential cell therapy product. The other potential outcome from completion of this study is that it would pave the way for use of macrophage cell therapy in other forms of ALF.

Any intellectual property arising during this program would be appropriately protected with the input of the University and partners (Scottish National Blood Transfusion). Furthermore, the University of Edinburgh has a strong record of exploiting innovative research findings through commercialization of intellectual property. To maximize the scientific and clinical impact from this regenerative medicine the investigators will closely involve the UK Advanced Therapy Network of which Campbell and Forbes are members. The investigators have a record of publishing in high impact journals with wide readership in the relevant scientific and clinical communities.
The MRC Centre for Regenerative Medicine has a strong outreach program which will help disseminate results to appropriate patient groups and stakeholders.