Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure

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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