Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies

重新定义血液系统恶性肿瘤中的噬血细胞性淋巴组织细胞增多症

基本信息

批准号：
10112637
负责人：
Michael Jordan
金额：
$ 18.58万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112637
关键词：
Adult Affect Antibodies CD8-Positive T-Lymphocytes Child Clinical Clinical Trials Collection Complement Complication Data Development Diagnostic Disease Etoposide Flow Cytometry Functional disorder Future Gene Expression Genetic Hematologic Neoplasms Immune Immune checkpoint inhibitor Incidence Infection Inflammation Inflammatory Interferon Type II Interferon-beta International Knowledge Left Lesion Life Lymphocyte Lymphoma Malignant - descriptor Malignant Neoplasms Mutation Pathogenesis Pathologic Pathway interactions Patient-Focused Outcomes Patients Phenotype Predictive Value of Tests Production Proteomics Sampling Sepsis Serum Subgroup Syndrome T-Cell Activation T-Lymphocyte Therapeutic Toxic effect Tumor Immunity Validation anti-cancer base cancer immunotherapy cohort conventional therapy cytotoxic experience experimental study familial hemophagocytic lymphohistiocytosis immune activation improved outcome individualized medicine insight macrophage monocyte novel therapeutics perforin peripheral blood profiles in patients response targeted treatment therapy development treatment strategy

项目摘要

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that is increasingly recognized in patients with malignancies (M-HLH). However, nearly early everything that is known about its pathophysiology and treatment is derived from clinical and scientific studies related to familial HLH (FHL). Though FHL and M-HLH have clear clinical similarities, it is not known whether they have similar pathophysiol- ogy. Indeed, even though M-HLH has been recognized for decades, we know nearly nothing about its patho- physiology. To remedy this gap, we have assembled an international group of collaborators and a unique set of patient-derived samples that will allow us to compare serum proteomic profiles and immune cellular pheno- types of patients with FHL, M-HLH, uncomplicated malignancies (U-M), and other inflammatory conditions in ways that are likely to yield broad new insights into HLH. Based on the clear clinical similarities between M- HLH and FHL, it is likely that some M-HLH patients will be quite similar to FHL, even though M-HLH patients are diverse enough to encompass multiple distinct mechanisms. Thus, we hypothesize that M-HLH is a com- posite syndrome, including: 1.) patients in which the malignant clone is essentially `mimicking' FHL; 2.) patients with T cell hyperactivation and `hyper-interferonemia' which is recognizably similar to FHL, and; 3.) patients with substantial innate immune dysregulation, which is dissimilar to FHL but not yet classifiable (see Figure 1). Furthermore, we hypothesize that FHL-like T cell hyperactivation represents a new paraneoplastic immune syndrome and may define patients who would benefit from targeted anti-IFN-g therapy developed for FHL, as well as anti-cancer immunotherapies, such as immune checkpoint inhibitors. Aim 1. Define the distinctive serum proteomic profiles of patient groups within M-HLH. We will employ a robust proteomic platform (SomaScan) to assess samples from patients with M-HLH, comparing to the groups listed above. We will develop classifiers to distinguish M-HLH from U-M and define M-HLH subgroups in an exploratory cohort and test the predictive value of these classifiers in a validation cohort. Aim 2. Define the incidence of `FHL-like' T cell activation profiles in M-HLH. We have recently identified a clear CD8+ T cell profile in FHL, which readily distinguishes HLH from another highly inflamed state, bacterial sepsis. We will utilize flow cytometry to analyze the peripheral blood T cell profiles of the patient groups above, focusing on those with proteomic profiles most similar to FHL. We will also compare T cell and monocyte gene expression profiles of these patient groups. These cellular studies will provide valuable cross-validation, com- plementing the proteomic characterization above 1

淋巴淋巴虫组织细胞增多症（HLH）是一种威胁生命的炎症综合征，越来越多在恶性肿瘤患者（M-HLH）中识别。但是，几乎很早就知道它的一切病理生理学和治疗来自与家族性HLH（FHL）有关的临床和科学研究。尽管FHL和M-HLH具有明显的临床相似性，但尚不知道它们是否具有相似 OGY。确实，即使M-HLH已被认可了数十年，我们几乎对其病情一无所知生理。为了弥补这一差距，我们组建了一组国际合作者和一组独特的合作者患者衍生的样品将使我们能够比较血清蛋白质组学特征和免疫细胞肉体患有FHL，M-HLH，单纯性恶性肿瘤（U-M）和其他炎症状况的患者类型可能会产生对HLH的广泛见解的方式。基于M-之间的明显临床相似性 HLH和FHL，即使M-HLH患者也可能与FHL非常相似，即使M-HLH患者也可能非常相似多样化足以包含多种不同的机制。因此，我们假设M-HLH是一个 Posite综合征，包括：1。）恶性克隆本质上是“模仿” FHL的患者； 2.）患者与T细胞过度激活和“过度疗法血症”，与FHL相似，并且； 3.）患者具有实质性的先天免疫失调，这与FHL不同，但尚未分类（请参阅图 1）。此外，我们假设FHL样T细胞过度激活代表了一种新的副塑性免疫综合征并可能定义将从针对FHL开发的靶向抗IFN-G疗法中受益的患者以及抗癌免疫疗法，例如免疫检查点抑制剂。目标1。定义M-HLH中患者组的独特血清蛋白质组学特征。我们将采用一个与两组相比上面列出。我们将开发分类器以区分M-HLH和U-M并在一个中定义M-HLH子组探索性队列并测试这些分类器在验证队列中的预测价值。 AIM 2。定义M-HLH中“ FHL样” T细胞激活谱的发生率。我们最近确定了 FHL中清晰的CD8+ T细胞谱，很容易区分HLH与另一个高度发炎的细菌败血症。我们将利用流式细胞仪分析上述患者组的外周血T细胞谱，专注于那些与FHL最相似的蛋白质组学特征的人。我们还将比较T细胞和单核细胞基因这些患者组的表达谱。这些细胞研究将提供有价值的交叉验证，将上面的蛋白质组学表征置 1