Macrophage cell therapy for liver cirrhosis

Liver disease is the third leading cause of premature death in the UK, with deaths increasing by 400% since 1970. Currently the only curative option for end-stage liver disease is liver transplantation. 

The new treatment being developed involves taking cells from the blood of patients and turning them into macrophages in the lab using chemical signals.  The new cells are then re-injected into the patient with the hope of rebuilding the damaged organ from within.

Previous research, undertaken by Professor Forbes and his research team, has shown that macrophages (large white blood cells which have the ability to “eat” bacteria) can help to reduce scarring and stimulate regeneration of the liver. This research was pre-clinical research, with tests performed on mice in the laboratory.

A phase one clinical trial has now been completed, with the new treatment tested on patients for the first time. This was a safety trial, and so it is not possible to draw any conclusions regarding the effectiveness of the new treatment from it, however results published in October 2019 have confirmed the safety and feasibility of a macrophage cell therapy for liver disease.

Professor Forbes and his team are now conducting a phase two clinical trial, to assess how well the new treatment works. During this phase, patients are randomised to either receive the macrophages or to receive the best standard care available. The team will measure whether the treatment helps to reduce scarring and improves liver function. They should know the results of this phase 2 trial in 2021, depending on how well patient recruitment goes.   

Q&A with Professor Stuart Forbes

What is liver cirrhosis?

Liver cirrhosis is the end stage of chronic liver disease that can be due to many causes. In the Western world this can be due to alcohol, obesity or hepatitis viruses but there are also many other causes such as auto immune disease. It’s a very common cause of death in Scotland - up to 1 in 50 deaths – and there’s been a large increase in morbidity and mortality from cirrhosis, unlike many other chronic diseases.

What are the current treatment options for liver cirrhosis?

Transplantation is currently the only effective treatment for end-stage liver cirrhosis. However, this is severely limited by organ availability so we desperately need new treatments for people with established cirrhosis. 

What are macrophages and how can they help treat liver cirrhosis?

Macrophages are cells that eat dead material in the body and help fight infections but recently researchers have found that they are able to break down scar tissue and in fact stimulate regeneration in tissue - such as the liver - and help coordinate the regenerative response in those organs. This is particularly the case when the liver is overcoming whatever has damaged it, so it’s in recovery that they are particularly effective.

What is this new research into a new treatment?

We have undertaken the first trial to use macrophages as a cell therapy for liver disease. The trial was based on our previous work on a mouse model of chronic liver disease, conducted at CRM, which found that these macrophages helped to reduce scarring and stimulate regeneration. 

This was a Phase 1 safety trial in patients with established liver cirrhosis. The team separated blood cells called monocytes from the patient’s blood through a process called apheresis. These cells differentiated it into macrophages of a similar variety that found to stimulate regeneration in mice. 

What does the treatment involve?

The patient comes to be screened, to find out if their suitable for the study. The treatment involves the patient being connected to a cell separation or Apheresis Unit. The Apheresis Unit separates the monocytes (macrophage precursors) from the rest of the blood. This takes two or three hours. Those monocytes are then taken to the GMP facility where SNBTS differentiate them into regenerative macrophages in a process that takes a week. One week later the patient comes back to the Apheresis Unit and is infused with those cells via a vein in their arm. The macrophages home to the liver, where we hope that they will help to repair the damage. 

What has your research shown?

Our research has so far confirmed the safety and feasibility of a macrophage cell therapy for liver disease. This was a safety study and so we can’t talk about whether the treatment will work or not at this stage. However, the study has shown that with increasing doses of cells that this was well tolerated and had no significant adverse clinical problems. 

What’s next?

We can’t talk about effectiveness, but we can say that the phase 2 trial has now started in Edinburgh. This is where patients are randomised to either receive the macrophages or to receive the best standard care available. The team will measure whether this helps the liver to reduce scarring, regenerating improved function. They should know the results of this phase 2 trial within a year. They have recruited about 50% of the target 52 patients and is about to be rolled out in Glasgow and Dundee (and subsequently other sites across the UK). 

Can patients take part in a trial?

Currently patients with established cirrhosis are signed up to the trial via clinicians within NHS Lothian. Soon this trial will be open to patients in Dundee and Glasgow, however there are complex selection criteria and they will once again be signed up via clinicians. Patients cannot sign up to take part in a trial via the Centre for Regenerative Medicine.

Who has been involved in this research?

The Scottish National Blood Transfusion Service have partnered with us on this research. They’ve helped take our basic laboratory findings through to the clinic by helping to produce these cells to Good Manufacturing Practice in our in-house Cell Therapy Facility, in other words, in a format that we can give to patients. 

This work has been conducted at Edinburgh BioQuarter, within the Centre for Regenerative Medicine, where we have integrated basic researchers and clinicians. The BioQuarter has a cell separation unit and the clinical research facility a few metres from the liver transplant unit and the liver wards. This integration has made it ideal to do this research at Edinburgh BioQuarter.

How was this research funded?

This work was supported by a Medical Research Council UK grant (Biomedical Catalyst Major Awards Committee, Reference: MR/M007588/1) to Prof. Stuart Forbes: https://gtr.ukri.org/projects?ref=MR%2FM007588%2F1   

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