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

最严重的血癌往往不能单靠化疗治愈。对于这些癌症，一种叫做同种异体干细胞移植的治疗方法被使用。同种异体sct涉及将血液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已经建立并在常规临床实践中，全球每年约进行20000例Allo-SCT。同种异体sct治疗的最常见疾病是急性髓性白血病（AML），一种侵袭性成人血癌。同种异体细胞移植如何治愈患者？虽然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“看到”患者的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，就会产生益处。这被称为移植物抗白血病（GvL）。然而，供体免疫细胞也会攻击并损害患者的正常健康组织。这就是移植物抗宿主病（GvHD）。介导GvL和GvHD的主要免疫细胞被称为T细胞。尽管同种异体细胞移植可以治愈，但它有严重的副作用。鉴于此，同种异体细胞移植通常仅限于70岁以下的患者；但即便如此，仍有10-40%的患者死于手术相关的死亡，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%的患者在同种异体细胞移植后治愈。进行同种异体细胞移植的原因是，如果没有它，大多数患者将在6个月内死亡。那么我们如何改善同种细胞移植的结果呢？我们知识中最重要的空白之一是，我们不知道患者细胞上触发供体免疫细胞攻击导致GvL和/或GvHD的蛋白质的身份。识别和激活免疫细胞的蛋白质被称为抗原。该项目的中心目标是鉴定在接受同种异体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、创新的方法，以一种公正的方式识别触发GvL和GvHD的抗原，使用来自成功进行同种异体sct的AML患者及其供体的样本。在两组患者-供体配对中，他们发现患者细胞上的这些抗原能被供体T细胞识别。他们还发现了T细胞（T细胞受体）上识别这些抗原的蛋白质。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细胞中时，它们可以使新的供体T细胞对抗原产生反应。通过这种方式，实验室已经开发出一套完整的工作流程来鉴定可能触发GvL和GvHD的抗原以及介导GvL和GvHD的T细胞群。在这个项目中我要做什么？现在，我将在13对AML患者-供体对的更大组中测试该工作流。我会识别所有能被供体T细胞识别的抗原，这些抗原存在于病人细胞中。然后，我将测试这些抗原在临床上是否重要——可以预防疾病复发（即可能触发GvL）和/或可能引起GvHD，通过测试一个非常大的患者-供体对队列。然后，我将分离出识别可能引发GvL的临床上最重要的3种抗原的T细胞受体。最后，我将测试它们是否能识别抗原，以及是否能杀死AML细胞。该项目可以为患者提供更精确的供体匹配-供体可以提供治疗性GvL反应，同时避免/最小化GvHD。它还可以详细跟踪引起GvL和GvHD的同种异体细胞移植后的T细胞。最后，它可能导致新的T细胞疗法只促进GvL。这项工作的好处在学术受益人部分中更完整地列出。

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.