Elucidating genetics of response to immune checkpoint blockade in lung cancer

阐明肺癌免疫检查点阻断反应的遗传学

基本信息

批准号：
10470607
负责人：
Timothy An-thy Chan
金额：
$ 41.88万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-18 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470607
关键词：
Accounting Affinity Aftercare Animal Model Apoptotic Archives Autologous Binding Biological Markers CD8-Positive T-Lymphocytes Cancer Etiology Cancer Model Cell Cycle Cells Cessation of life Characteristics Clinical Clonality Clustered Regularly Interspaced Short Palindromic Repeats Collection Data Disease remission Drug resistance Foundations Freezing Future Genetic Genomics Goals Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunologic Monitoring Immunologics Immunotherapy Implant In Vitro Informatics Kinetics Lead Light Lymphoma Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mus Mutate Mutation Nivolumab Non-Small-Cell Lung Carcinoma PTEN gene Pathologic Pathway interactions Patients Phenotype Pre-Clinical Model Resistance Resistance development Sampling Shapes Smoking Specimen T cell response T-Cell Receptor T-Lymphocyte Testing Time Tumor Escape Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Validation Work anti-CTLA4 anti-PD-1 anti-PD1 therapy base cancer therapy collaborative approach cytokine exhaustion exome genetic analysis genome-wide analysis immune checkpoint blockade immune resistance immunogenic immunogenicity improved outcome innovation insight ipilimumab mouse model multidisciplinary mutant neoantigens new technology nonsynonymous mutation patient oriented research patient subsets pembrolizumab peripheral blood power analysis pressure programmed cell death ligand 1 programmed cell death protein 1 relapse prediction responders and non-responders response restoration tumor tumor microenvironment

项目摘要

Abstract Immune checkpoint inhibitors like ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) are revolutionizing cancer treatment. Understanding the genetic basis of response and resistance to immune checkpoint inhibitors are critical for improving outcomes with current agents and for developing new ones. Patients can undergo dramatic remissions after treatment while others reap no benefit. Furthermore, the immune phenotype shows substantial temperospatial variability and is influenced by multiple variables. The rationale of this project is that there is a fundamental genetic basis underlying response to immune checkpoint inhibitors that is poorly understood. Our preliminary data demonstrates that response to immune checkpoint blockade is strongly determined by the tumor mutation landscape and dictated by a specific neoantigen repertoire. We will apply a conceptually and technically innovative, systematic, multidisciplinary, and highly collaborative approach to elucidate the neoantigen landscape underlying response to immune checkpoint inhibitors. Our contribution here is expected to provide unparalleled mechanistic detail on how immune checkpoint inhibitors function and to provide biomarkers to identify patients who will benefit from PD-1 blockade. Furthermore, building on data showing that resistance may be mediated by immune pressure and immunoediting, we will shed light into how resistance to these drugs develop, providing definitive evidence for causal mechanisms of anti-tumor immunity. Should our work succeed, we envision substantial utility for similar studies for other cancers. Such an understanding will provide great insight into the mechanisms underlying how immune checkpoint blockade works, provide much needed precise biomarkers, and establish a foundation to develop more effective immunotherapy.

抽象的免疫检查点抑制剂，例如ipilimumab（抗CTLA4）和nivolumab（抗PD1）革命性的癌症治疗。了解反应和抵抗的遗传基础免疫检查点抑制剂对于改善当前药物的结果至关重要开发新的。患者可以在治疗后发生急剧的缓解，而其他人则无需益处。此外，免疫表型显示出很大的温度可变性，是受多变量的影响。该项目的理由是有一个基本的遗传对免疫检查点抑制剂的基础反应尚未理解。我们的初步数据表明，对免疫检查点封锁的反应由肿瘤强烈确定突变景观，由特定的新抗原曲目决定。我们将在概念上应用以及技术创新，系统的，多学科和高度协作的方法阐明对免疫检查点抑制剂的新抗原景观。我们的预计此处的贡献将提供有关免疫检查点的无与伦比的机械细节抑制剂功能并提供生物标志物，以识别将受益于PD-1封锁的患者。此外，基于数据，表明电阻可能是由免疫压力和免疫程序，我们将阐明对这些药物的抵抗力的发展，提供确定性抗肿瘤免疫的因果机制的证据。如果我们的工作成功，我们想象针对其他癌症类似研究的实质性实用性。这样的理解将提供深刻的见识进入免疫检查点封锁工作方式的基础机制，提供急需的精确的生物标志物，并为开发更有效的免疫疗法建立基础。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape.

DOI：
10.1186/s13073-022-01146-3
发表时间：
2022-12-19
期刊：
Genome medicine
影响因子：
12.3
作者：
通讯作者：

Panel-based estimates of tumor mutational burden: characterizing unknown unknowns.

基于小组的肿瘤突变负荷估计：描述未知的未知因素。

DOI：
10.1093/annonc/mdz234
发表时间：
2019
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
0
作者：
Yang,W;Morris,LGT;Chan,TA
通讯作者：
Chan,TA

Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types.