Minimal residual disease characteristics and its immune system interaction in the context of treatment resistance

治疗耐药背景下的微小残留病特征及其免疫系统相互作用

• 批准号: 468966010
• 负责人: Professorin Dr. Monika Brüggemann
• 金额: --
• 依托单位: Hämatologie Labor Kiel / Sektion für hämatologische Spezialdiagnostik
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/468966010?language=en
• 关键词: Minimal; residual; disease; characteristics; its

Minimal residual disease (MRD) is the most important prognostic factor in acute lymphoblastic leukemia (ALL). Highly sensitive MRD measurement by molecular or flow cytometric methods allows accurate assessment of treatment response and enables prediction of an impending relapse. Most data on MRD kinetics have been collected for ALL patients receiving conventional chemotherapy. Novel treatment approaches as immunotherapies are expanding the treatment landscape in ALL and show fundamentally different MRD and relapse dynamics compared to conventional chemotherapy. However, persistence of MRD defines a group of patients with high risk of relapse irrespective of treatment type. Thus, better understanding mechanisms of MRD persistence under both treatment types is of huge clinical importance.Studies addressing potential resistance mechanisms to different therapeutic regimens are often performed using pretherapeutic leukemia samples. Only few studies focus on residual leukemia under treatment and its crosstalk with the immune system. However, these insights are highly relevant to specifically target and eliminate relapse initiating MRD cells. For example, using mathematical models, we could show that modifying treatment protocols based on the growth rates of residual leukemic cells delayed relapse and eradicated MRD. Besides tumor specific factors, the crosstalk between leukemia and the immune system might play a crucial role in the elimination of residual disease. Leukemic cells may develop mechanisms to escape immune recognition or to suppress the immune system, especially relevant for outcome under immunotherapy. Therefore, our goal within the proposed project is to accurately characterize and compare both MRD cells and the immune system under chemotherapy and immunological approaches in the context of treatment resistance. To this end, we will select samples from MRD good and poor responders under both forms of therapy from the large MRD dataset available in Kiel, and first accurately immunophenotype these samples by multicolor flow cytometry, looking at both leukemia and healthy cells. We will then isolate tumor cells and the different immune cell compartments and study their molecular profiles, in selected cases even at the single cell level. Further, we will validate our results on large patient cohorts by multicolor flow cytometry, also considering the markers that have been identified as relevant in other projects. We hope that these studies will provide detailed understanding of leukemia and host-dependent mechanisms of MRD-persistence under chemo- and immunotherapy and help to delineate factors associated with eradication of MRD. Our analyses will support the development of therapy protocols with optimized sequences and combinations of classical chemotherapy and immunological approaches to eradicate MRD and to improve the chances of cure for ALL patients.

微小残留病（MRD）是急性淋巴细胞白血病（ALL）最重要的预后因素。通过分子或流式细胞术方法进行高灵敏度MRD测量，可以准确评估治疗反应并预测即将复发。大多数关于MRD动力学的数据都是针对接受常规化疗的ALL患者收集的。新的治疗方法，如免疫疗法，正在扩大急性淋巴细胞白血病的治疗领域，与传统化疗相比，显示出根本不同的MRD和复发动态。然而，MRD的持续存在定义了一组复发风险高的患者，无论治疗类型如何。因此，更好地了解两种治疗类型下MRD持续存在的机制具有重要的临床意义。针对不同治疗方案的潜在耐药机制的研究通常使用治疗前白血病样本进行。很少有研究关注治疗中的残留白血病及其与免疫系统的相互作用。然而，这些见解与特异性靶向和消除引发MRD细胞复发高度相关。例如，使用数学模型，我们可以证明根据残留白血病细胞的生长速度修改治疗方案可以延迟复发并根除MRD。除了肿瘤特异性因素外，白血病与免疫系统之间的串扰可能在消除残留疾病中发挥重要作用。白血病细胞可能发展出逃避免疫识别或抑制免疫系统的机制，特别是与免疫治疗的结果相关。因此，我们提出的项目的目标是准确地表征和比较化疗和免疫方法下的MRD细胞和免疫系统在治疗耐药性的背景下。为此，我们将从基尔可用的大型MRD数据集中选择两种治疗形式下的MRD良好反应和不良反应样本，并首先通过多色流式细胞术准确地对这些样本进行免疫表型分析，同时观察白血病细胞和健康细胞。然后，我们将分离肿瘤细胞和不同的免疫细胞区室，并研究它们的分子谱，在选定的情况下，甚至在单细胞水平。此外，我们将通过多色流式细胞术在大型患者队列中验证我们的结果，同时考虑到在其他项目中已确定的相关标记物。我们希望这些研究将提供对白血病和化疗和免疫治疗下MRD持续存在的宿主依赖机制的详细了解，并有助于描述与MRD根除相关的因素。我们的分析将支持治疗方案的发展，优化序列和经典化疗和免疫方法的组合，以根除MRD，提高ALL患者的治愈机会。