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

噬血细胞性淋巴组织细胞增多症 (HLH) 是一种危及生命的炎症综合征，其发病率越来越高在恶性肿瘤患者 (M-HLH) 中得到认可。然而，几乎早期人们对它的了解病理生理学和治疗源自与家族性 HLH (FHL) 相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，但尚不清楚它们是否具有相似的病理生理学特征。奥吉。事实上，尽管 M-HLH 已被认识数十年，但我们对其致病性几乎一无所知。生理。为了弥补这一差距，我们组建了一个国际合作者小组和一套独特的患者来源的样本使我们能够比较血清蛋白质组谱和免疫细胞表型患有 FHL、M-HLH、无并发症的恶性肿瘤 (U-M) 和其他炎症性疾病的患者类型这些方法可能会给 HLH 带来广泛的新见解。基于 M- 之间明显的临床相似性 HLH 和 FHL，一些 M-HLH 患者可能与 FHL 非常相似，即使 M-HLH 患者足够多样化以涵盖多种不同的机制。因此，我们假设 M-HLH 是一个阳性综合征，包括： 1.) 恶性克隆本质上“模仿”FHL 的患者； 2.) 患者具有 T 细胞过度激活和“高干扰素血症”，这与 FHL 相似； 3.) 病人具有严重的先天免疫失调，这与 FHL 不同，但尚未分类（见图 1).此外，我们假设 FHL 样 T 细胞过度激活代表了一种新的副肿瘤免疫综合征，并可能定义哪些患者将从针对 FHL 开发的靶向抗 IFN-g 疗法中受益，如以及抗癌免疫疗法，例如免疫检查点抑制剂。目标 1. 定义 M-HLH 中患者组独特的血清蛋白质组谱。我们将聘请一名强大的蛋白质组学平台 (SomaScan) 用于评估 M-HLH 患者的样本，并与各组进行比较上面列出了。我们将开发分类器来区分 M-HLH 和 U-M，并定义 M-HLH 子组探索性队列并在验证队列中测试这些分类器的预测价值。目标 2. 确定 M-HLH 中“FHL 样”T 细胞激活谱的发生率。我们最近确定了一个 FHL 中清晰的 CD8+ T 细胞谱，可轻松将 HLH 与另一种高度炎症状态（细菌性状态）区分开来败血症。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，重点关注那些与 FHL 最相似的蛋白质组谱。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，补充上述蛋白质组表征 1