Immunogenomic determinants of response and resistance to neoadjuvant anti-PD-1 in resectable NSCLC

可切除 NSCLC 中新辅助抗 PD-1 反应和耐药的免疫基因组决定因素

基本信息

批准号：
10358604
负责人：
Kellie Nicole Smith
金额：
$ 37.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358604
关键词：
Address Adjuvant Chemotherapy Antigens Bar Codes Bioinformatics Biological Markers Biology CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cancer Patient Cell physiology Cells Cessation of life Characteristics Clinical Clinical Trials Colon Carcinoma Curative Surgery Data Development Diagnosis Disease Epitopes Excision Future Gene Expression Gene Expression Profile Genetic Genetic Transcription Goals Helper-Inducer T-Lymphocyte Human Image Immune Immune response Immunogenomics In Situ Hybridization Infiltration Intrinsic factor Knowledge LRRC32 gene Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Molecular Neoadjuvant Therapy Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome Outcome Study PD-1 blockade Pathologic Pathway interactions Patient-Focused Outcomes Patients Persons Phase II Clinical Trials Population Regulatory T-Lymphocyte Relapse Resectable Residual state Resistance Resistance development Role Somatic Mutation Specificity T cell receptor repertoire sequencing T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Technology Testing Time Tissues Tumor Burden Tumor Immunity Tumor-Derived anti-PD-1 antigen-specific T cells cancer diagnosis combinatorial cytotoxic differential expression effector T cell immune checkpoint blockade immune resistance improved innovation malignant breast neoplasm neoantigens novel novel strategies prevent programmed cell death protein 1 programs response response biomarker single cell sequencing spatial relationship standard care success transcriptome sequencing treatment response tumor tumor specificity

项目摘要

Summary More than 1.8 million people worldwide are diagnosed with non-small cell lung cancer (NSCLC) every year. Of these patients, 20% present with stage I or II disease. For these patients, surgical resection remains the first course of treatment, however even in apparently curative surgery 50% of stage I and 70% of stage II NSCLC patients will recur and eventually die of the disease. Neoadjuvant and adjuvant chemotherapy are standard treatments for resectable NSCLC and are used with the dual goals of reducing tumor size prior to surgery and preventing relapse. We recently completed a clinical trial of neoadjuvant PD-1 blockade in resectable NSCLC and demonstrated an impressive 45% major pathologic response rate. To date, however, the mechanisms underlying response to this treatment are unknown. In the study proposed here, we will leverage this existing clinical trial and the biospecimens already obtained to elucidate the functional impact of PD-1 blockade on tumor-reactive T cells and to determine how differential T cell transcriptional programs facilitate pathologic response. We will implement a novel approach, using the T cell receptor as a molecular barcode for antigen-specificity using basic and single cell sequencing technologies, to understand the dynamic interplay of different T cell subsets and how their transcriptional programming is modified by anti- PD-1. Identification of targetable markers of response or resistance, development of novel bioinformatic approaches to analyze neoantigen-specific single cell data, and enumeration of immunogenomic determinants of pathologic response to neoadjuvant PD-1 blockade are only some of the key outcomes of this study.

概括每年，全世界有超过180万人被诊断出患有非小细胞肺癌（NSCLC）。在这些患者中，有20％出现I或II期疾病。对于这些患者，手术切除仍然是第一个治疗过程，但是即使在显然治愈手术中，第I期的50％和II期的70％ NSCLC患者将复发并最终死于该疾病。新辅助和辅助化疗是可切除NSCLC的标准治疗方法，用于减小肿瘤大小之前的双重目标手术并防止复发。我们最近完成了新辅助PD-1封锁的临床试验可切除的NSCLC表现出令人印象深刻的45％主要病理反应率。但是，迄今为止对该处理的反应的基础机制尚不清楚。在这里提出的研究中，我们将利用现有的临床试验和已经获得的生物测量来阐明肿瘤反应性T细胞上的PD-1阻断，并确定差异T细胞转录程序的差异促进病理反应。我们将使用T细胞受体作为分子来实现一种新的方法使用基本和单细胞测序技术的抗原特异性条形码，以了解不同T细胞子集的动态相互作用，以及如何通过抗 - 修改其转录编程 PD-1。识别响应或抗性的目标标记，新生物信息学的发展分析新抗原特异性单细胞数据的方法和免疫基因组的枚举对新辅助PD-1封锁的病理反应的决定因素只是某些关键结果这项研究。