Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure

检查点抑制剂可恢复肝衰竭患者的单核细胞/巨噬细胞功能

• 批准号: MR/W015412/1
• 负责人: Mark Thursz
• 金额: $ 106.9万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW015412%2F1
• 关键词: Checkpoint; Inhibitors; Restore; Monocyte; Macrophage

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

肝衰竭可能发生在以前肝脏健康的人（急性肝衰竭）或肝硬化患者（急性失代偿）。无论原因如何，肝功能衰竭是一种严重的医疗紧急情况，可能会发展为其他器官（包括肾脏，心脏，肺和大脑）的衰竭和死亡。肝功能衰竭患者由于免疫系统功能丧失而非常容易感染。感染会使肝功能衰竭恶化，增加死亡的风险。我们最近在肝功能衰竭的动物模型中发现了免疫功能下降的原因之一。在该模型中，肝脏中的免疫细胞（称为巨噬细胞）及其循环对应物单核细胞无法清除血液中的细菌。因此，细菌能够在全身传播并引起感染。在该模型中，我们能够使用一种名为Nivolumab的药物来逆转免疫缺陷，该药物目前用于治疗某些类型的癌症。我们有初步证据表明，肝衰竭患者中也存在巨噬细胞和单核细胞的同样问题。这项研究计划旨在调查Nivolumab是否能够逆转肝衰竭患者中观察到的免疫缺陷。首要任务是确定Nivolumab在肝功能衰竭患者中的安全性。Nivolumab已被证明在少数患者中引起肝脏炎症，这可能会加剧肝功能衰竭。然而，Nivolumab可重复用于癌症患者，而我们仅建议使用单次剂量。为了评估安全性，我们将给少数患者服用小剂量的Nivolumab，并仔细随访6个月。为了证明Nivolumab恢复免疫功能，我们将在治疗前后仔细检查血液中的单核细胞。虽然我们也想看看巨噬细胞的功能，但这是不可行的，因为它们只能在肝脏组织中找到，并且当肝脏仍在体内时，它们的功能无法测试。除了测试对Nivolumab的免疫反应外，我们还希望研究这种治疗是否可以降低感染风险。肝功能衰竭患者始终处于感染的密切监测之下，因此我们将能够测量与我们通常预期的感染率相比，治疗是否降低了感染率。有一种蛋白质（sPD-L1）从免疫细胞释放到血液中，这似乎是免疫功能障碍的强烈指标。测量这种蛋白质比检查单核细胞的功能要容易得多，因此我们建议探索sPD-L1水平是否会告诉我们哪些患者可能从纳武利尤单抗治疗中受益。如果这些研究成功，我们将期望使用它们来指导临床试验的设计，以测试纳武利尤单抗是否可以用作肝衰竭患者治疗的一部分