Graft versus Leukaemia (GvL): Identification & characterisation of GVL antigens and cognate T cell responses in Acute Myeloid Leukaemia

移植物抗白血病 (GvL)：鉴定

• 批准号: MR/W015846/1
• 负责人: Bing Shian Tseu
• 金额: $ 38.49万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FW015846%2F1
• 关键词: Graft; versus; Leukaemia; GvL; Identification

The most aggressive blood cancers often cannot be cured by chemotherapy alone. For these cancers a curative treatment called allogenic stem cell transplantation or allo-SCT is used. Allo-SCT involves transfer of blood stem and immune cells from a healthy person (donor) to a patient (recipient). Allo-SCT is well-established and in routine clinical practice since the 1960s. ~20000 allo-SCTs are performed worldwide annually. The most common disease treated by allo-SCT is Acute Myeloid Leukaemia (AML), an aggressive adult blood cancer. How does allo-SCT cure patients? Though donor cells are matched closely to patient cells to avoid the donor cells being rejected by the patient, donor cells are not identical to patient cells. Therefore, the donor cells can "see" the patient's cells as foreign and attack them. This has both beneficial and adverse consequences. The benefit arises when donor immune cells attack and eradicate the patient's blood cancer. This is called graft versus leukaemia (GvL). However, donor immune cells can also attack and damage the patient's normal healthy tissue. This is known as graft versus host disease (GvHD). The principal immune cells mediating GvL and GvHD are called T cells. Though allo-SCT is curative it has serious side effects. Given this, allo-SCT is usually restricted to patients under the age of 70 years of age; but even then 10-40% of patients die of procedure-related mortality, often related to GvHD or infection. Furthermore, ~20-40% of patients still die of disease relapse. Thus, only 30-70% of patients are cured after allo-SCT. The reason why allo-SCT is performed is because without it most patients will die within 6 months.So how can we improve allo-SCT outcomes? One of the most important gaps in our knowledge is that we do not know the identity of the proteins on a patient's cells that trigger donor immune cells to attack them resulting in GvL and/or GvHD. Proteins that recognise and activate immune cells are called antigens. The central aim of this project is to identify the antigens that trigger GvL and GvHD in an AML patient who has received an allo-SCT. The laboratories I will be working in have developed a novel, innovative approach to identify antigens that trigger GvL and GvHD, in an unbiased manner, using samples from AML patients who have had a successful allo-SCT, and their donors. In two patient-donor pairs they have shown these antigens on the patient's cells are recognised by donor T cells. They have also identified the proteins on the T cells (T cell receptors) that recognise these antigens. Finally, when they introduced these antigen-reactive T cell receptors into T cells from a different donor, they could make the new donor T cells respond to antigen. In this way the laboratories have developed a complete workflow to identify antigens that may trigger GvL and GvHD and the T cells populations that mediate GvL and GvHD.What will I do in this project? I will now test this workflow on a larger group of 13 AML patient-donor pairs. I will identify all the antigens that could be recognised by donor T cells, that are present on patient cells. I will then test if these antigens are clinically important - could prevent disease relapse (i.e. may be triggering GvL) and/or could be causing GvHD by testing a very large cohort of patient-donor pairs. I will then isolate the T cell receptors recognising 3 of the most clinically important antigens that may be triggering GvL. Finally, I will test if they recognise the antigen and if that leads to killing of AML cells.This project could lead to more precise matching of donors for patients - donors that could provide a curative GvL response whilst avoiding/minimising GvHD. It could also allow detailed tracking of T cells post allo-SCT that cause GvL and GvHD. Finally, it could result in new T cell therapies that just promote GvL. The benefits of this work are set out more completely in the Academic Beneficiaries section.

最具侵袭性的血癌通常不能单独通过化疗治愈。对于这些癌症，使用称为同种异体干细胞移植或allo-SCT的治愈性治疗。Allo-SCT涉及将造血干细胞和免疫细胞从健康人（供体）转移到患者（受体）。自20世纪60年代以来，Allo-SCT已被广泛应用于常规临床实践。全球每年进行约20000例allo-SCT。allo-SCT治疗的最常见疾病是急性髓细胞白血病（AML），一种侵袭性成人血癌。allo-SCT如何治愈患者？尽管供体细胞与患者细胞紧密匹配以避免供体细胞被患者排斥，但供体细胞与患者细胞并不相同。因此，供体细胞可以“将”患者的细胞视为外来细胞并攻击它们。这既有有利的后果，也有不利的后果。当供体免疫细胞攻击并根除患者的血癌时，这种益处就会出现。这被称为移植物抗白血病（GvL）。然而，供体免疫细胞也可以攻击和损害患者的正常健康组织。这被称为移植物抗宿主病（GvHD）。介导GvL和GvHD的主要免疫细胞被称为T细胞。虽然allo-SCT是治愈性的，但它有严重的副作用。鉴于此，allo-SCT通常仅限于70岁以下的患者;但即使如此，仍有10-40%的患者死于手术相关死亡，通常与GvHD或感染有关。此外，约20-40%的患者仍死于疾病复发。因此，只有30-70%的患者在allo-SCT后治愈。allo-SCT之所以要进行，是因为如果不进行allo-SCT，大多数患者将在6个月内死亡。那么，我们如何改善allo-SCT的结局？我们知识中最重要的差距之一是我们不知道患者细胞上触发供体免疫细胞攻击它们导致GvL和/或GvHD的蛋白质的身份。识别和激活免疫细胞的蛋白质称为抗原。该项目的主要目的是确定在接受allo-SCT的AML患者中触发GvL和GvHD的抗原。我将工作的实验室已经开发出一种新颖的创新方法，以公正的方式识别触发GvL和GvHD的抗原，使用来自成功进行allo-SCT的AML患者及其供体的样本。在两个患者-供体对中，他们显示患者细胞上的这些抗原被供体T细胞识别。他们还鉴定了T细胞上识别这些抗原的蛋白质（T细胞受体）。最后，当他们将这些抗原反应性T细胞受体引入来自不同供体的T细胞时，他们可以使新的供体T细胞对抗原产生反应。通过这种方式，实验室开发了一个完整的工作流程，以识别可能触发GvL和GvHD的抗原以及介导GvL和GvHD的T细胞群。我现在将在一个更大的13对AML患者-供体组中测试这个工作流程。我将鉴定出所有能被捐赠者T细胞识别的抗原，这些抗原存在于患者细胞上。然后，我将测试这些抗原是否具有临床重要性-可以预防疾病复发（即可能引发GvL）和/或可能通过测试非常大的患者-供体对队列导致GvHD。然后，我将分离识别3种可能触发GvL的临床上最重要的抗原的T细胞受体。最后，我将测试他们是否识别抗原，以及这是否会导致AML细胞的杀伤。该项目可能会导致更精确的患者供体匹配-供体可以提供治疗性GvL反应，同时避免/最大限度地减少GvHD。它还可以允许详细跟踪导致GvL和GvHD的allo-SCT后的T细胞。最后，它可能导致新的T细胞疗法，只是促进GvL。这项工作的好处在学术受益人部分更完整地阐述。