权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating Immune Responses to Neoantigen Cancer Vaccines using In Vivo Functionalized Lineage

使用体内功能化谱系研究对新抗原癌症疫苗的免疫反应

基本信息

批准号：
10558688
负责人：
Camila Robles-Oteiza
金额：
$ 8.87万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558688
关键词：
Address Advanced Development Antigen Presentation Antigen Presentation Pathway Antitumor Response Automobile Driving Biological Models Biopsy CD8B1 gene Cancer Etiology Cancer Patient Cancer Vaccines Carcinogens Categories Cell physiology Cessation of life Clinical Clinical Research Correlation Studies DNA Replication Proofreading Defect Disease Disseminated Malignant Neoplasm Enzymes Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Harvest Human Immune Immune checkpoint inhibitor Immune response Immunotherapy K-ras mouse model Lung Adenocarcinoma MHC Class I Genes Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Methods Minority Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenic Patients Peripheral Phase Positioning Attribute Postdoctoral Fellow Research Resistance Signal Transduction Site Survival Rate T cell infiltration T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Tumor Immunity Vaccines Work anti-PD-1 cancer therapy cancer type candidate validation checkpoint inhibition checkpoint therapy chemotherapy exome sequencing experimental study human disease improved in vivo innovation insight mouse model mutant neoantigen vaccine neoantigens neoplastic cell nonsynonymous mutation novel patient derived xenograft model patient population personalized therapeutic pre-clinical programmed cell death protein 1 programs resistance mechanism response single-cell RNA sequencing standard of care targeted treatment therapeutic vaccine tissue resident memory T cell tool tumor tumor growth tumor microenvironment vaccine development

项目摘要

Project Summary Lung cancer is the leading cause of cancer related deaths worldwide, demonstrating the pressing need for effective and lasting treatments. Immune checkpoint inhibitors, which block negative regulators of T cell function, have the potential to generate lasting responses in lung cancer patients. However, only a minority of patients respond to these therapies and ~50% of patients whose tumors initially respond to therapy eventually develop acquired resistance. Clinical studies have identified correlations between tumor non-synonymous mutation burden and response to immune checkpoint inhibitors across multiple cancer types. However, most existing pre-clinical mouse models of lung cancer do not recapitulate the complexity of mutational landscapes in human cancers, and importantly, the tumors in these models do not respond to immune checkpoint inhibition. Due in part to the lack of available models, mechanisms of primary and acquired resistance to immune checkpoint inhibition in lung cancer are not fully understood and strategies to overcome resistance are lacking. To address this challenge, we developed novel orthotopic mouse models of Kras mutant lung adenocarcinoma that recapitulate features of human disease essential for studying tumor-immune interactions, including the tumor mutational landscape as well as responsiveness and acquired resistance to immune checkpoint inhibition. Using these novel models of murine lung cancer, my goal is to investigate mechanisms of resistance to these new widely-used lung cancer therapies (F99 phase). I will test the overarching hypothesis that diverse genetic alterations and transcriptional programs resulting in antigen presentation defects and neoantigen loss are major mechanisms of acquired resistance to ICIs and that these drive the emergence of tumor-cell extrinsic features of resistance in the tumor microenvironment. I will investigate the spectrum of genetic and transcriptional drivers of acquired resistance, focusing on defects in antigen processing and presentation (Aim 1.2.A). I will also investigate whether neoantigen loss can mediate acquired resistance in lung cancer (Aim 1.2.B). As a post-doc (K00 phase), I plan to work on approaches to improve immunotherapies for lung cancer to expand their benefits to a broader patient population than those who currently benefit, specifically by investigating the efficacy of personalized neoantigen vaccines that induce tissue resident memory T cells (Aim 2). The aims described here will identify drivers of resistance to checkpoint therapy and explore methods to use neoantigen vaccines in patients that currently do not benefit from approved immunotherapies, yielding strategies to expand immunotherapy benefits to a broader patient pool.

项目总结