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：
10209167
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/10209167
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 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.

概括全球每年有超过 180 万人被诊断患有非小细胞肺癌 (NSCLC)。这些患者中，20% 患有 I 期或 II 期疾病。对于这些患者来说，手术切除仍然是首选第一个疗程，但即使在明显治愈的手术中，I 期的 50% 和 II 期的 70% NSCLC患者会复发并最终死于该病。新辅助化疗和辅助化疗是可切除非小细胞肺癌的标准治疗方法，其双重目标是在术前缩小肿瘤大小手术并预防复发。我们最近完成了一项新辅助 PD-1 阻断的临床试验可切除的 NSCLC 并表现出令人印象深刻的 45% 主要病理缓解率。然而，迄今为止，这种治疗的潜在反应机制尚不清楚。在这里提出的研究中，我们将利用现有的临床试验和已获得的生物样本来阐明其功能影响 PD-1 对肿瘤反应性 T 细胞的阻断并确定 T 细胞转录程序的差异促进病理反应。我们将实施一种新方法，使用 T 细胞受体作为分子使用基本和单细胞测序技术进行抗原特异性条形码，以了解不同 T 细胞亚群的动态相互作用以及它们的转录编程如何被抗 PD-1。识别响应或抗性的靶向标记，开发新型生物信息学分析新抗原特异性单细胞数据和免疫基因组计数的方法新辅助 PD-1 阻断的病理反应的决定因素只是一些关键结果这项研究。