Effect of autologous macrophage therapy in cirrhosis in response to individual immune reparative pathways: developing a novel therapy

BACKGROUND: Liver cirrhosis is the end stage of any injury process to the liver. Once established it inevitably progresses to complications such as portal hypertension, cancer and death. There is not cure for liver cirrhosis besides liver transplant. We face an unmet demand for treatment of this condition. The role of macrophages in fibrosis development and resolution in the liver has been extensively investigated. Prof Forbes group invested in the development of autologous macrophage product to promote fibrosis resolution hence cirrhosis regression. This has demonstrated its efficacy and safety in animal models. From these encouraging pre-clinic data a phase 1 first in human clinical trial of autologous activated macrophage product for cirrhotic patients was developed. METHODS: Using an established 3+3 dose escalation model we enrolled a total of 9 subject in the phase 1 trial reaching a maximum achieved and safe dose of 1x10^9 macrophages. In addition to adverse events, dose toxicity and macrophage activation syndrome (MAS) parameter, we evaluated a varied range of circulating cytokines and chemokine pre and post treatment using a commercial kit. Moreover we developed a protocol for P13- magnetic resonance spectrometry (MRS) for the analysis of the metabolically active liver parenchyma. Data from the phase 1 trial were used to improve the autologous cellular produce and phase 2 randomised controlled trial. RESULTS: The autologous activated macrophage produce is demonstrated not to cause any toxicity in this first in human study of cirrhotic population of different aetiology. Cytokine and chemokine analysis supports these findings and specifically demonstrates low levels of IL-8, which represent cardinal feature of MAS. Other interesting cytokine signals may support extra cellular matrix remodelling effect of the autologous macrophage product infusion. In addition we demonstrated a reproducible protocol for MRS in liver disease. DISCUSSION: Autologous activated macrophage infusion did not result in any toxicity in cirrhotic subjects taking part in this study and shows preliminary signs of efficacy in fibrosis resolution both clinically and biochemically. This work places the basis of development of cellular products for treatment of cirrhosis and fibrosis and provides invaluable insight in immune response to cellular treatment.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2024

Author dc:creator

• Moroni, Francesca

Advisors dc:contributor.advisor

• Forbes, Stuart
• Fallowfield, Jonathan

• liver disease treatment
• cirrhosis
• macrophages
• macrophage activation syndrome
• fibrosis

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/4171

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/41439