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

项目摘要/摘要-项目1 尽管免疫检查点抑制物(ICI)治疗在临床上取得了巨大的成功，但只有~20%的非 小细胞肺癌(NSCLC)患者对抗PD1/PDL1治疗有反应。在努力改善这一点上 数字，该领域已经启动了800多项临床试验(涉及所有癌症类型)，测试新的治疗方法 结合免疫检查站封锁。实际上，这些试验都没有充分解决 中性粒细胞谱系是ICI治疗失败的重要因素。我们提供的初步数据是 中性粒细胞是非小细胞肺癌中最常见的免疫细胞类型，与CD8细胞含量呈负相关， 并排除干扰素γ签名的存在，先前表明这与有利的脑梗塞治疗相关 回应。我们将对患者的FFPE切片数据集进行多重免疫组织化学 用抗PD1/PDL1治疗表明中性粒细胞与不良预后相关。我们用一本小说 肿瘤包含数百个突变以识别ICI机制决定因素的小鼠模型 治疗反应和测试一种新的CXCR1/CXCR2拮抗剂与抗PDL1治疗协同作用。最后， 我们将进行第二阶段临床试验，测试新型CXCR1/CXCR2拮抗剂(SX-682， Syntrix生物系统公司)和nivolumab用于既往抗肿瘤治疗失败的晚期非小细胞肺癌患者 PD1/PDL1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.