Targetable Immune Evasion Pathways in Hodgkin Lymphoma

霍奇金淋巴瘤的靶向免疫逃避途径

基本信息

批准号：
9176760
负责人：
Margaret A Shipp
金额：
$ 41.09万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-22 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176760
关键词：
9p24.1 Address Adult Antigen Presentation Antigen-Presenting Cells Appearance Autologous B-Cell Lymphomas B-Lymphocytes Biological Markers Biopsy Specimen Blocking Antibodies Cell Survival Clinical Clinical Trials Clonality Combined Modality Therapy Custom Cytometry Data Development Diagnosis Diagnostic Disease Employee Strikes Evaluation Event Formalin Frequencies Genetic Hodgkin Disease Hybrids Immune Immunotherapy Incidence Ligands MHC Class I Genes Malignant - descriptor Malignant lymphoid neoplasm Mediastinal Metabolism Mutation Natural Killer Cells Neoadjuvant Therapy Outcome PDCD1LG1 gene Paraffin Embedding Pathway interactions Patient Agents Patients Peripheral Blood Mononuclear Cell Pilot Projects Receptor Signaling Recurrence Reed-Sternberg Cells Refractory Regimen Relapse Resistance Series Signal Transduction Sorting - Cell Movement Specimen Stem cell transplant Suspension substance Suspensions T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Time Translating base cell type chemotherapeutic agent deep sequencing design exhaustion exome sequencing experience follow-up genetic analysis insight macrophage monocyte neoplastic cell prognostic significance receptor response therapeutic target tool transcription factor tumor tumor microenvironment

项目摘要

Project Summary Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, one of the main lymphoid malignancies to strike young and otherwise healthy adults, classical Hodgkin lymphoma (cHL), is largely defined by its morphologic appearance and treated with an empiric combination of available chemotherapeutic agents. We previously hypothesized that 9p24.1/PD-L1/PD-L2 copy number alteration (CNA) was a genetic mechanism of immune evasion in cHL and considered the PD-1 pathway to be a rational therapeutic target in this disease. After defining recurrent 9p24.1 copy gain and increased PD-L1/PD-L2 expression as high-frequency events in cHL, we explored the clinical activity of PD-1 blockade in this lymphoid malignancy. In independent pilot studies of two different PD-1 blocking agents, patients with multiply relapsed/refractory cHL experienced remarkable clinical responses that were often durable. In our competitive renewal application, we propose to build on these findings with the following specific aims: 1.0) Determine the relationship between PD-L1/PD-L2 alterations and outcome, response to PD-1 blockade and additional genetic bases of immune evasion in cHL; 2.0) Elucidate mechanisms of response and resistance to PD-1 blockade in cHL patients; 3.0) Develop a comprehensive approach to analyze genetic bases for immune evasion in cHL; and 4.0) Define the clinical activity of PD-1 blockade at earlier timepoints in the treatment of cHL. The proposed studies, will define complementary and/or confounding genetic bases of immune evasion and mechanisms of response and resistance to PD-1 blockade and inform our incorporation of PD-1 blockade into the standard therapy of cHL.

项目摘要我们目前的诊断和治疗淋巴恶性肿瘤的方法不能反映新兴的数据关于致病机制和相关理性治疗靶标。例如，主要之一淋巴性恶性肿瘤可打击年轻且健康健康的成年人，经典的霍奇金淋巴瘤（CHL）是在很大程度上取决于其形态学外观，并通过可用的经验组合处理化学治疗剂。我们先前假设9p24.1/pd-l1/pd-l2复制号码变更（CNA）是CHL中免疫逃避的遗传机制，并认为PD-1途径是合理的该疾病的治疗靶标。定义复发9p24.1复制增益并增加PD-L1/PD-L2之后作为CHL中的高频事件的表达，我们探索了PD-1阻滞的临床活性恶性。在对两种不同的PD-1阻断剂的独立试验研究中，患者多重复发/难治性CHL经历了显着的临床反应，通常耐用。在我们的竞争中续订应用，我们建议以以下特定目的建立这些发现：1.0）确定 PD-L1/PD-L2改变与结果，对PD-1封锁的反应和其他遗传之间的关系 CHL中免疫逃避的基础； 2.0）阐明了对PD-1阻滞的响应和抗性机制 CHL患者； 3.0）开发了一种分析CHL免疫逃避的遗传基础的综合方法；和4.0）定义PD-1在CHL治疗中早期时间点上的临床活性。这拟议的研究将定义免疫逃避和/或混杂的遗传基础的免疫逃避和/或对PD-1封锁的响应和抵抗力的机制，并告知我们将PD-1封锁纳入 CHL的标准疗法。