Project 1: Targeting the Neutrophil Lineage To Enhance Immune Checkpoint Inhibitor Efficacy in NSCLC

项目概要/摘要-项目1 虽然免疫检查点抑制剂（ICI）治疗已经取得了巨大的临床成功，但只有约20%的非免疫检查点抑制剂治疗。 小细胞肺癌（NSCLC）患者对抗PD 1/PDL 1治疗有反应。为了改善这一点， 据统计，该领域已经启动了800多项临床试验（涵盖所有癌症类型），测试新的治疗方法， 与免疫检查点阻断结合。实际上，这些审判都没有充分解决 中性粒细胞谱系是ICI治疗失败的重要因素。我们提供了初步数据， 中性粒细胞是NSCLC中最普遍的免疫细胞类型，与CD 8细胞含量呈负相关， 并排除干扰素γ信号的存在，以前显示与有利的ICI治疗相关 反应我们将对从患者中获得的FFPE切片数据集进行多重免疫组织化学 用抗PD 1/PDL 1治疗，以显示中性粒细胞与不良结局相关。我们利用一本小说 小鼠模型，其中肿瘤含有数百个突变，以确定ICI的机制决定因素 治疗反应，并测试新型CXCR 1/CXCR 2拮抗剂与抗PDL 1治疗的协同作用。最后， 我们将进行2期临床试验以测试新的CXCR 1/CXCR 2拮抗剂（SX-682， Syndrome Biosystems，Inc.）和nivolumab治疗既往抗-HCV治疗失败的晚期NSCLC患者， PD 1/PDL 1治疗。

Project Summary/Abstract – Project 1 Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non- small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. In efforts to improve upon this figure, the field has launched over 800 clinical trials (across all cancer types) testing novel therapeutics in conjunction with immune checkpoint blockade. Effectively none of these trials adequately address the neutrophil lineage as a substantial contributor to ICI treatment failure. We provide preliminary data that neutrophils are the most prevalent immune cell type in NSCLC, inversely correlate with CD8 cellular content, and preclude the presence of the IFNγ signature, previously shown to correlate with favorable ICI treatment response. We will perform multiplex-immunohistochemistry on a dataset of FFPE slides obtained from patients treated with anti-PD1/PDL1 therapy to show that neutrophils associate with poor outcomes. We utilize a novel mouse model in which the tumor harbors hundreds of mutations to identify the mechanistic determinants of ICI treatment response and test a novel CXCR1/CXCR2 antagonist to synergize with anti-PDL1 treatment. Lastly, we will perform a Phase 2 clinical trial testing the combination of the novel CXCR1/CXCR2 antagonist (SX-682, Syntrix Biosystems, Inc.) and nivolumab in advanced stage NSCLC patients who have previously failed anti- PD1/PDL1 therapy.