Targetable Immune Evasion Pathways in Hodgkin Lymphoma

项目摘要 我们目前诊断和治疗淋巴系统恶性肿瘤的方法没有反映出新的数据 关于致病机制和相关的合理治疗目标。例如，其中一个主要的 淋巴系统恶性肿瘤发生在年轻人和其他健康的成年人，经典霍奇金淋巴瘤(Chl)，是 很大程度上由其形态外观定义，并以可用 化疗药物。我们先前假设9p24.1/PD-L1/PD-L2拷贝数改变 (CNA)是CHL免疫逃避的一种遗传机制，认为PD-1途径是合理的 这种疾病的治疗靶点。在定义了经常性9p24.1拷贝增益和增加的PD-L1/PD-L2之后 作为CHL中的高频事件，我们探讨了PD-1拮抗剂在该淋巴组织中的临床活性 恶毒。在两种不同PD-1阻滞剂的独立先导研究中，患有多发性硬化的患者 复发/难治性慢性粒细胞白血病经历了显著的临床反应，通常是持久的。在我们的竞争中 关于续签申请，我们建议以这些调查结果为基础，以下列具体目标为基础：1.0)确定 PD-L1/PD-L2改变与预后、PD-1阻断反应及额外基因的关系 Chl；2.0免疫逃逸的基础)阐明对PD-1阻断的反应和抵抗机制 慢性淋巴细胞性白血病患者；3.0)开发一种全面的方法来分析慢性淋巴细胞性白血病免疫逃避的遗传基础； 和4.0)确定PD-1阻滞剂在CHL治疗早期时间点的临床活性。这个 拟议的研究将定义免疫逃避和/或免疫逃避的互补和/或混淆的遗传基础 PD-1阻滞剂的反应和抵抗机制及提示我们将PD-1阻滞剂加入 慢性粒细胞白血病的标准治疗。

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.