Targetable Immune Evasion Pathways in Hodgkin Lymphoma

项目摘要 我们目前的诊断和治疗淋巴系统恶性肿瘤的方法并没有反映新出现的数据 探讨其发病机制和合理的治疗靶点。例如，主要的 淋巴恶性肿瘤袭击年轻人和其他健康成人，经典霍奇金淋巴瘤（cHL）， 很大程度上由其形态学外观来定义，并使用现有的经验性组合进行治疗。 化疗剂。我们以前假设9p24.1/PD-L1/PD-L2拷贝数改变 (CNA)是cHL免疫逃避的遗传机制，并认为PD-1通路是一种合理的免疫逃避机制。 治疗的目标。在定义复发性9p24.1拷贝增加和PD-L1/PD-L2增加后 作为cHL中的高频事件，我们探索了PD-1阻断在这种淋巴细胞中的临床活性， 恶性肿瘤在两种不同PD-1阻断剂的独立初步研究中， 复发性/难治性cHL经历了显著的临床反应，通常是持久的。调整竞技 更新申请，我们建议建立在这些调查结果与以下具体目标：1.0）确定 PD-L1/PD-L2改变与结局、对PD-1阻断的应答和其他遗传因素之间的关系 cHL中免疫逃避的基础; 2.0）阐明cHL中对PD-1阻断的应答和抵抗机制， 3.0）开发一种全面的方法来分析cHL中免疫逃避的遗传基础; 和4.0）在治疗cHL的较早时间点定义PD-1阻断的临床活性。的 拟议的研究将确定免疫逃避的互补和/或混杂遗传基础， 对PD-1阻断的应答和抗性机制，并告知我们将PD-1阻断纳入 cHL的标准疗法

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.