Macrophage cell therapy: a new hope for chronic liver disease patients

3d illustration of Abstract medical background with Diseased liver

What are the main challenges currently faced in the treatment of chronic liver diseases, and how does Resolution Therapeutics aim to address these challenges?

Once a patient develops advanced cirrhosis/end-stage liver disease there are no specific therapies to significantly avoid major decompensations and death in the next few years. This is caused by the high amounts of inflammation and fibrosis (scarring) in the liver, suppressing the liver’s natural ability to regenerate or perform its function of filtering blood. Resolution plans to address this by directly decreasing inflammation and improving liver function using the patient’s own macrophages. Delivered as an autologous cell therapy, these macrophages have been engineered to increase their anti-inflammatory and anti-fibrotic properties, with the aim of delivering more potent and durable clinical effect to patients with end-stage liver disease.

What pre-clinical evidence supports the efficacy of macrophage cell therapy in treating liver diseases, and how has this informed Resolution Therapeutics’ approach?

Our approach is based on over 15 years of pre-clinical studies in vitro and in vivo, performed at the University of Edinburgh and other institutions: state of the art models of liver fibrosis were utilised to demonstrate the phenotype and role of pro-regenerative macrophages in the improvement of liver fibrosis. Further, the same models were applied to test the anti-fibrotic potential of mouse pro-regenerative macrophages used in a therapeutic setting. Our academic founders at the university of Edinburgh used these data to support regulatory filings with the UK Health Authorities for the MATCH Phase I and II studies, which have provided strong proof of concept data regarding the potential of macrophage therapy to treat cirrhosis in humans: non-engineered macrophages were shown to significantly increase survival and transplant-free survival in a Phase II randomised parallel group trial of 50 patients with cirrhosis.

The preclinical findings, together with the early evidence of tolerability and efficacy coming from the MATCH Phase I study, laid the foundations for our characterisation and engineering platform, used to develop Resolution Therapeutics’ lead product, which will be tested in patients starting later this year.

Could you describe the platform of macrophage biology and cell engineering used by Resolution Therapeutics in developing their cell therapies?

The patient’s own monocytes, a type of white blood cell, are removed via an apheresis procedure. We then incubate the cells to mature into ‘pro-regenerative’ macrophages and insert two RNA messages to produce two human proteins that will be expressed at the site of injury when these ‘engineered’ macrophages are given back to the patient.

Resolution has recently been granted clinical trial authorisation (CTA) approval from the Medicines and Healthcare products Regulatory Agency (MHRA) for our EMERALD Phase I/II study which will begin in Q3 2024. This study will investigate the safety and efficacy of our engineered macrophage cell therapy in patients with decompensated liver cirrhosis.

What potential impact could macrophage cell therapy have on the need for liver transplantation and the overall management of end-stage liver disease?

Our goal is to obviate the need for liver transplantation for many, but more importantly to extend and improve the lives of end-stage liver disease (ESLD) patients, most of whom will not have the opportunity to have a liver transplant. This is reflected in the MATCH data recently presented at the European Association for the Study of the Liver (EASL), where two patients in the control group had a liver transplant and seven patients died, whereas there were no liver transplants and only two deaths in the treated group.

Are there other conditions that Resolution Therapeutics aims to treat with their macrophage cell therapy approach?

The general principle of ‘anti-inflammatory’ macrophages treating fibrotic diseases is applicable to many organs and Resolution is in the early stages of exploring how our macrophage platform may be suitable for chronic kidney injury, pulmonary fibrosis and chronic graft versus host disease (GVHD).

Reference

¹ Brennan P et al., J Hep, 2024 (EASL ILC 2024 Abstract #LBP-007). Available from: https://www.journal-of-hepatology.eu/article/S0168-8278(24)00574-9/abstract