MICA: A randomised, double blind, controlled mechanistic study of obinutuzumab versus rituximab in ANCA-associated vasculitis (ObiVas)

MICA：一项关于 obinutuzumab 与利妥昔单抗治疗 ANCA 相关血管炎 (ObiVas) 的随机、双盲、对照机制研究

• 批准号: MR/W015544/1
• 负责人: Rachel Jones
• 金额: $ 153.93万
• 依托单位: University of Cambridge
• 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%2FW015544%2F1
• 关键词: MICA; randomised; double; blind; controlled

What is vasculitis?Vasculitis is a rare medical condition that affects around 250 per million people in the UK. It is characterised by inflammation and damage to the walls of blood vessels. Blood vessels carry blood around the body supplying our organs with oxygen and nutrients. Thus, any organ can be affected by vasculitis, but some organs are affected more than others. For example, the kidneys, lungs, ear nose and throat regions are commonly affected. Vasculitis is a so-called 'auto-immune' disease where the body's own immune system attacks itself (blood vessels in this case) instead of defending them against infection. Without treatment, inflammation causes the affected organs to stop working. Patients can become very unwell and can die if proper treatment is not started quickly. Research has shown that a certain type of immune cell (B cell) produces Y-shaped proteins (antibodies called ANCAs) which are important in starting the inflammation. We also know that another cell type (T cell) seems to be overactive and misbehaving in patients with vasculitis. The problem.The current best treatment is a medicine called rituximab, which is given directly in the vein by a drip. Rituximab gets rid of B cells from the blood. Patients feel better quite quickly after rituximab, but after about 6-12 months, the inflammation starts up again, so more and more rituximab is needed, which can cause unwanted effects to the immune system in the long-term. Our solution.We have looked at samples of tissue taken from the inside of the nose in patients who have received rituximab. We have shown that B cells are still present, suggesting that rituximab is not working as well as we need it to. Furthermore, we have used cutting-edge genetic analysis to show that B cells in the nose are interacting with the T cells. Our theory is that the inability of rituximab to get rid of the B cells in the tissues, allows the mechanisms driving the disease to continue which is why rituximab cannot make the vasculitis go away for a very long time. There is a new medicine called obinutuzumab that also targets B cells but has been engineered to use slightly different mechanisms. Animal studies show greater reductions of B cells in tissues compared to rituximab, and clinical trials in humans have shown that obinutuzumab works well for some blood cancers and another autoimmune disease (lupus). We think that using obinutuzumab in patients with vasculitis will lead to better targeting of B cells in the tissues, resulting in less interaction between B cells and T cells, and better control of vasculitis and inflammation. We propose a small experimental study of rituximab versus obinutuzumab in patients with vasculitis. We will give 6 patients the normal medicine and 6 patients the new medicine. Each patient will have a biopsy of the inside of the nose before treatment and 3 months after treatment. We will be able to assess the effects of the two medicines in terms of their ability to get rid of the B cells inside the nose and the indirect effect this has on the T cells. We will then follow patients up for 2 years by which time the B cells should have returned in the blood. Through regular blood tests, we will be able to examine the type of the returning B cells, and whether or not obinutuzumab has made them less likely to cause the vasculitis and inflammation to return. Importance and wider use. This study will let us assess and compare the mechanism of action of these 2 medicines, and also dig deep into the processes that drive inflammation in the disease tissue. This is an important study because finding a better treatment than rituximab will improve the lives of patients with vasculitis. Furthermore, targeting B cells is a commonly used approach for many other diseases, so the findings of this study may improve the understanding and treatments of other autoimmune diseases.

什么是血管炎？血管炎是一种罕见的疾病，在英国影响约250万人。它的特征是炎症和对血管壁的破坏。血管周围携带血液，为我们的器官提供氧气和养分。因此，任何器官都会受到血管炎的影响，但某些器官比其他器官更受影响。例如，通常会影响肾脏，肺，耳鼻和喉咙区域。血管炎是一种所谓的“自身免疫”疾病，人体自身的免疫系统会攻击自己（在这种情况下是血管），而不是捍卫它们免受感染的侵害。没有治疗，炎症会导致受影响的器官停止工作。如果没有快速开始适当的治疗，患者可能会变得非常不适，可能会死亡。研究表明，某种类型的免疫细胞（B细胞）会产生Y形蛋白（称为ANCAS），这对于开始炎症很重要。我们还知道，血管炎患者的另一种细胞类型（T细胞）似乎过度活跃和表现不佳。问题。当前的最佳治疗方法是一种称为利妥昔单抗的药物，它是通过滴水直接在静脉中给出的。利妥昔单抗从血液中摆脱B细胞。利妥昔单抗后，患者感觉很快好，但是大约6-12个月后，炎症再次开始，因此需要越来越多的利妥昔单抗，这可能会对免疫系统造成不良影响。我们的解决方案。我们研究了接受利妥昔单抗的患者中从鼻子内部采集的组织样本。我们已经证明B细胞仍然存在，这表明利妥昔单抗的工作状态不如我们需要。此外，我们已经使用了尖端的遗传分析表明鼻子中的B细胞与T细胞相互作用。我们的理论是，利妥昔单抗无法摆脱组织中的B细胞，使驱动疾病的机制继续下去，这就是为什么利妥昔单抗无法使血管炎持续很长时间。有一种称为obinutuzumab的新药物也靶向B细胞，但已设计用于使用略有不同的机制。动物研究表明，与利妥昔单抗相比，组织中B细胞的降低较大，人类的临床试验表明，obinutuzumab对某些血液癌和另一种自身免疫性疾病（狼疮）的效果很好。我们认为，在血管炎患者中使用obinutuzumab会导致组织中B细胞的更好靶向，从而减少B细胞与T细胞之间的相互作用，并更好地控制血管炎和炎症。我们提出了一项针对血管炎患者利妥昔单抗与obinutuzumab的小型实验研究。我们将为6名患者提供正常药物，并将6例患者提供新药物。每位患者在治疗前和治疗后3个月都对鼻子内部进行活检。我们将能够从两种药物中消除鼻子内的B细胞的能力以及对T细胞产生的间接效果的能力来评估这两种药物的影响。然后，我们将跟踪患者2年，与之相关的B细胞应在血液中恢复。通过常规的血液检查，我们将能够检查回返回的B细胞的类型，以及obinutuzumab是否使它们引起血管炎和炎症的可能性较小。重要性和更广泛的用途。这项研究将使我们评估和比较这两种药物的作用机理，并深入研究驱动疾病组织炎症的过程。这是一项重要的研究，因为找到比利妥昔单抗更好的治疗方法将改善血管炎患者的生活。此外，靶向B细胞是许多其他疾病的常用方法，因此这项研究的发现可以改善对其他自身免疫性疾病的理解和治疗。