Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure
Lead Research Organisation:
Imperial College London
Department Name: Metabolism, Digestion and Reproduction
Abstract
Liver failure may occur in people with previously healthy livers (acute liver failure) or in patients with cirrhosis (acute decompensation). Irrespective of the cause, liver failure is a serious medical emergency which may progress to failure of other organs (including the kidneys, heart, lungs and brain) and death. Patients with liver failure are incredibly susceptible to infection due to loss of function in their immune system. Infection makes the liver failure worse and increases the risk of dying.
We have recently found one of the causes of reduced immune function in an animal model of liver failure. In the model immune cells resident in the liver, called macrophages, and their circulating counterparts, monocytes, are unable to clear bacteria from the blood. The bacteria are therefore able to disseminate throughout the body and cause infection. In the model we were able to reverse the immune defect using a drug called Nivolumab which is currently used to treat some types of cancer. We have preliminary evidence that the same problem with macrophages and monocytes occurs in patients with liver failure.
This programme of research sets out to investigate whether Nivolumab is able to reverse the immune defect seen in patients with liver failure. The first priority will be to establish the safety of Nivolumab in patients with liver failure. Nivolumab has been shown to cause liver inflammation in a minority of patients which could potentially exacerbate liver failure. However, Nivolumab is given repeatedly for patients with cancer whereas we only propose to use a single dose. In order to assess safety we will give a small number of patient a small dose of Nivolumab and follow them carefully for 6 months.
In order to demonstrate that Nivolumab restores immune function we will carefully examine monocytes from blood before and after treatment.
Although we would also like to look at the function of the macrophages, this is not feasible as they can only be found in liver tissue and their function cannot be tested whilst the liver is still in the body.
In addition to testing the immune response to Nivolumab we also wish to investigate whether this treatment reduces the risk of infection. Patients with liver failure are always kept under close surveillance for infection so we will be able to measure whether the rate of infection is reduced by treatment compared to the rate of infection that we would normally expect.
There is a protein (sPD-L1) released into the blood from immune cells which appears to be a strong indicator of immune dysfunction. It is a lot easier to measure this protein than to examine the function of monocytes so we propose to explore whether sPD-L1 levels will tell us which patients might benefit from treatment with Nivolumab.
If these studies are successful we would expect to use them to inform the design of a clinical trial to test whether Nivolumab could be used as part of the treatment for patients with liver failure
We have recently found one of the causes of reduced immune function in an animal model of liver failure. In the model immune cells resident in the liver, called macrophages, and their circulating counterparts, monocytes, are unable to clear bacteria from the blood. The bacteria are therefore able to disseminate throughout the body and cause infection. In the model we were able to reverse the immune defect using a drug called Nivolumab which is currently used to treat some types of cancer. We have preliminary evidence that the same problem with macrophages and monocytes occurs in patients with liver failure.
This programme of research sets out to investigate whether Nivolumab is able to reverse the immune defect seen in patients with liver failure. The first priority will be to establish the safety of Nivolumab in patients with liver failure. Nivolumab has been shown to cause liver inflammation in a minority of patients which could potentially exacerbate liver failure. However, Nivolumab is given repeatedly for patients with cancer whereas we only propose to use a single dose. In order to assess safety we will give a small number of patient a small dose of Nivolumab and follow them carefully for 6 months.
In order to demonstrate that Nivolumab restores immune function we will carefully examine monocytes from blood before and after treatment.
Although we would also like to look at the function of the macrophages, this is not feasible as they can only be found in liver tissue and their function cannot be tested whilst the liver is still in the body.
In addition to testing the immune response to Nivolumab we also wish to investigate whether this treatment reduces the risk of infection. Patients with liver failure are always kept under close surveillance for infection so we will be able to measure whether the rate of infection is reduced by treatment compared to the rate of infection that we would normally expect.
There is a protein (sPD-L1) released into the blood from immune cells which appears to be a strong indicator of immune dysfunction. It is a lot easier to measure this protein than to examine the function of monocytes so we propose to explore whether sPD-L1 levels will tell us which patients might benefit from treatment with Nivolumab.
If these studies are successful we would expect to use them to inform the design of a clinical trial to test whether Nivolumab could be used as part of the treatment for patients with liver failure
Technical Summary
Liver failure is associated with increased susceptibility to infection which leads to multi-organ failure and increased mortality (1,2) . In an animal model of liver failure, innate immune system defects in monocyte/macrophage phagocytic function allowed circulating micro-organisms to disseminate and initiate sepsis (3). Blockade of the immunoregulatory molecule PD-1 restored phagocytosis in a rodent model of acute liver injury and in monocytes from patients with acute liver failure (4).
To determine whether PD-1 blockade exerts the desired therapeutic effect in-vivo we will treat patients with acute liver failure (N = 21) or acute decompensation of cirrhosis (N = 51) with the anti-PD-1 antibody, Nivolumab. Monocyte phenotype and phagocytic function will be measured ex-vivo using flow cytometry techniques and differences before and after treatment used to determine whether normal immune function is restored.
Safety of anti-PD-1 therapy will be explored in a sentinel cohort of patients treated with a 50% dose of Nivolumab and followed for 6 months.
The incidence of infection will be carefully documented in patients with acute decompensation and compared to the expected incidence (35%) to determine whether anti-PD-1 treatment exerts the desired effect on infection rates.
Macrophage PD-1 expression was associated with the level of soluble PD-L1 (sPD-L1) in plasma (4). We will therefore measure sPD-L1 in cohorts of patients with acute liver failure or acute decompensation to determine whether this biomarker will predict patients at enhanced risk of sepsis in order to potentially target anti-PD-1 therapy
To determine whether PD-1 blockade exerts the desired therapeutic effect in-vivo we will treat patients with acute liver failure (N = 21) or acute decompensation of cirrhosis (N = 51) with the anti-PD-1 antibody, Nivolumab. Monocyte phenotype and phagocytic function will be measured ex-vivo using flow cytometry techniques and differences before and after treatment used to determine whether normal immune function is restored.
Safety of anti-PD-1 therapy will be explored in a sentinel cohort of patients treated with a 50% dose of Nivolumab and followed for 6 months.
The incidence of infection will be carefully documented in patients with acute decompensation and compared to the expected incidence (35%) to determine whether anti-PD-1 treatment exerts the desired effect on infection rates.
Macrophage PD-1 expression was associated with the level of soluble PD-L1 (sPD-L1) in plasma (4). We will therefore measure sPD-L1 in cohorts of patients with acute liver failure or acute decompensation to determine whether this biomarker will predict patients at enhanced risk of sepsis in order to potentially target anti-PD-1 therapy
