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

项目1：靶向中性粒细胞谱系以增强非小细胞肺癌中免疫检查点抑制剂的功效

基本信息

批准号：
10174872
负责人：
A McGarry Houghton
金额：
$ 26.33万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174872
关键词：
Accounting Address Antibody Therapy Antigens Atypical lymphocyte Biopsy Specimen CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cancer Patient Cell Lineage Cells Cessation of life Clinical Clinical Trials Consent Core Biopsy Correlative Study Data Data Set Development Failure Fred Hutchinson Cancer Research Center Gene Expression Profile Genetically Engineered Mouse Goals Human IL8RA gene IL8RB gene Immune Immune checkpoint inhibitor Immune response Immune system Immunohistochemistry Immunotherapeutic agent Immunotherapy Interferon Type II Lung Lung Adenocarcinoma Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Genetics Mus Mutant Strains Mice Mutation Myelogenous Myeloid Cells Nivolumab Non-Small-Cell Lung Carcinoma Outcome PD-1/PD-L1 Patients Phase II Clinical Trials Phenotype Population Pre-Clinical Model Prospective cohort Retrospective cohort Safety Single Nucleotide Polymorphism Slide Smoke Solid Neoplasm Specimen Testing Therapeutic Tissues Treatment Efficacy Treatment Failure Work anti-PD-1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-PD1 antibodies anti-PD1 therapy base cancer type cell type checkpoint therapy cigarette smoke cigarette smoking co-clinical trial cohort design exhaust exhaustion immune checkpoint immune checkpoint blockade improved mortality mouse model nano-string neutrophil novel novel diagnostics novel therapeutics prevent prospective response small molecule success treatment response tumor tumor microenvironment

项目摘要

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.

项目总结/摘要 – 项目 1 尽管免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功，但只有约 20% 的非免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功。小细胞肺癌 (NSCLC) 患者对抗 PD1/PDL1 疗法有反应，正在努力改善这一点。如图所示，该领域已启动 800 多项临床试验（涵盖所有癌症类型），测试新疗法与免疫检查点封锁相结合，这些试验都没有有效地解决这一问题。我们提供的初步数据表明，中性粒细胞谱系是 ICI 治疗失败的一个重要因素。中性粒细胞是 NSCLC 中最常见的免疫细胞类型，与 CD8 细胞含量呈负相关，并排除 IFNγ 特征的存在，此前已证明该特征与有利的 ICI 治疗相关我们将对从患者获得的 FFPE 载玻片数据集进行多重免疫组织化学分析。我们利用抗 PD1/PDL1 疗法来证明中性粒细胞与不良结果相关。小鼠模型中的肿瘤含有数百个突变，以鉴定 ICI 的机制决定因素治疗反应并测试新型 CXCR1/CXCR2 拮抗剂与抗 PDL1 治疗的协同作用。我们将进行一项 2 期临床试验，测试新型 CXCR1/CXCR2 拮抗剂（SX-682、 Syntrix Biosystems, Inc.) 和 nivolumab 用于先前抗药治疗失败的晚期 NSCLC 患者 PD1/PDL1 治疗。