Preventing Acute Myeloid Leukaemia Relapse following Allogeneic Stem Cell Transplantation

干细胞移植是许多急性髓性白血病（AML）和其他血液和骨髓癌症患者的唯一治愈性疗法。然而，癌症复发仍然是最常见的死亡原因，并且是由于供体免疫系统未能消除残留疾病。最负责清除白血病的免疫细胞是T细胞。T细胞在复发时通常功能失调，白血病通常能够逃避它们。了解为什么T细胞变得功能失调，以及AML如何逃避它们，对于开发新的治疗方法，重新建立成功的免疫反应以治疗或预防复发至关重要。识别早期免疫功能障碍的患者也是必要的，以允许适当的新疗法的靶向。T细胞功能障碍发生在许多癌症和治疗，重新激活T细胞已经彻底改变了癌症护理。然而，当给予移植患者时，这些疗法引起显著的毒性。由于T细胞功能障碍有许多潜在的原因，因此重要的是要确定那些与对抗白血病的T细胞最相关的原因，以便在不引起不可接受的副作用的情况下靶向它们。为了了解供体T细胞如何变得功能失调，我们将研究移植后AML复发患者的数千个单个T细胞中的基因表达和DNA结构。这将使我们能够详细探索T细胞功能障碍时发生的变化，并确定患者功能障碍的主要驱动因素。靶向这些过程将成为治疗或预防移植后复发的新治疗策略的基础。AML经常显示参与T细胞活化的蛋白质，称为MHCII。表达通常在移植后复发时丢失，这降低了白血病激活T细胞的能力，提供了免疫逃避的机制。MHCII蛋白在AML中如何调节尚不清楚。AML是骨髓造血细胞的癌症。通过一个称为分化的过程，这些细胞通常会产生血液中发现的成熟细胞，其中一些强烈表达MHCII。这一过程在AML中被阻断，但可以通过最近开发的一类称为LSD 1抑制剂的药物重新建立。使用从患者样本中分离的白血病和T细胞，我们将研究这些药物驱动AML中MHCII表达和促进T细胞活化的能力。LSD 1抑制剂目前正在进行AML的临床试验，如果我们的结果支持其用于移植后复发，则为临床应用提供了明确的途径。在为患者提供新的预防性治疗之前，必须确定那些有复发风险的患者。最近的研究表明，功能失调的T细胞的早期检测可以预测复发。血液中蛋白质含量的变化也被观察到，反映了T细胞对白血病的活性。曼彻斯特是欧洲最大的临床蛋白质组学设施Stoller中心的所在地。我们能够分析成千上万的患者样本，并跟踪数百种血浆蛋白浓度的微小变化。我们已经建立了一项研究，在多个时间点从300名移植受者中收集血液样本。我们将使用这些样本来确定AML复发前血液蛋白含量和T细胞特性的变化，以开发新的预测性血液检测。总体而言，这项研究将确定导致干细胞移植后AML复发的免疫功能障碍和白血病免疫逃避的主要驱动因素。我们的研究结果将为治疗或预防疾病复发提供新的治疗策略。我们还将开发新的血液检测方法来预测AML复发，从而允许针对高危个体进行治疗并改善移植结果。

Stem cell transplantation is the only curative therapy for many patients with acute myeloid leukaemia (AML) and other cancers of the blood and bone marrow. However, cancer recurrence remains the most common cause of death, and is due to failure of the donor immune system to eliminate residual disease. The immune cells most responsible for clearing leukaemia are T cells. T cells are often dysfunctional at relapse, and leukaemia is frequently able to evade them. Understanding why T cells become dysfunctional, and how AML escapes them, is critical to the development of new treatments that re-establish successful immune responses to treat or prevent relapse. Identifying patients with early immune dysfunction is also necessary to allow appropriate targeting of novel therapies.T-cell dysfunction occurs in many cancers and treatments that re-invigorate T cells have revolutionised cancer care. However, these therapies cause significant toxicity when given to transplant patients. Because there are many potential causes of T-cell dysfunction, it is important to identify those most relevant to the T cells that fight leukaemia, in order to target them without causing unacceptable side effects. To understand how donor T cells become dysfunctional, we will study the expression of genes and the structure of DNA in thousands of individual T cells from patients with AML relapse after transplant. This will allow us to explore in detail the changes that occur as T cells become dysfunctional and identify the major drivers of dysfunction in patients. Targeting these processes will then form the basis of novel therapeutic strategies to treat or prevent post-transplant relapse.AML frequently displays proteins that are involved in the activation of T cells, called MHCII. Expression is often lost at post-transplant relapse and this reduces the ability of leukaemia to activate T cells, providing a mechanism of immune evasion. How MHCII proteins are regulated in AML is not known. AML is a cancer of the blood-forming cells of the bone marrow. Through a process termed differentiation these cells normally give rise to the mature cells found in blood, some of which strongly express MHCII. This process becomes blocked in AML, but can be re-established by a recently developed class of drugs called LSD1 inhibitors. Using leukaemia and T cells isolated from patient samples, we will investigate the ability of these drugs to drive MHCII expression in AML and promote T-cell activation. LSD1 inhibitors are currently in clinical trials for AML, providing a clear pathway to clinical application, should our results support their use for post-transplant relapse.Before novel preventative therapies can be given to patients, those at risk of relapse must be identified. Recent studies suggest that early detection of dysfunctional T cells may predict relapse. Changes in the protein content of blood have also been observed that reflect the activity of T cells against leukaemia. Manchester is home to the Stoller Centre, Europe's largest clinical proteomic facility. We are able to analyse thousands of patient samples and track small changes in the concentration of hundreds of plasma proteins. We have established a study to collect blood samples at multiple time points from 300 transplant recipients. We will use these samples to identify changes in the protein content of blood and the properties of T cells that precede AML relapse, in order to develop new predictive blood tests.Overall, this study will identify the major drivers of immune dysfunction and leukaemic immune evasion that lead to AML relapse after stem cell transplantation. Our results will inform new therapeutic strategies for treating or preventing disease recurrence. We will also develop new blood tests that predict AML relapse, allowing therapeutic targeting of at-risk individuals and improving transplant outcomes.