Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomized controlled trial

TY - JOUR

T1 - Autologous macrophage therapy for liver cirrhosis

T2 - a phase 2 open-label randomized controlled trial

AU - Brennan, Paul

AU - MacMillan, Mark

AU - Manship, Thomas A.

AU - Moroni, Francesca

AU - Glover, Alison

AU - Troland, Debbie

AU - MacPherson , Iain

AU - Graham, Catriona

AU - Aird, Rhona

AU - Semple, Scott I.

AU - Morris, David M.

AU - Fraser, Alasdair R.

AU - Pass, Chloe

AU - McGowan, Neil W. A.

AU - Turner, Marc L.

AU - Manson, Lynn

AU - Lachlan, Neil

AU - Dillon, John

AU - Kilpatrick, Alastair M.

AU - Campbell, John

AU - Fallowfield, Jonathan Andrew

AU - Forbes, Stuart J.

N1 - © 2025. The Author(s).

PY - 2025/3

Y1 - 2025/3

N2 - Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy (n = 27) compared to standard medical care (n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was -0.87 (95% confidence interval: -1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.

AB - Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy (n = 27) compared to standard medical care (n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was -0.87 (95% confidence interval: -1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.

KW - Liver cirrhosis

KW - macrophages

KW - cell therapy

KW - liver fibrosis

KW - liver regeneration

U2 - 10.1038/s41591-024-03406-8

DO - 10.1038/s41591-024-03406-8

M3 - Article

C2 - 39794616

SN - 1078-8956

VL - 31

SP - 979

EP - 987

JO - Nature Medicine

JF - Nature Medicine

IS - 3

M1 - 52

ER -