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

Liquid biopsy-based toolkits for neoantigen and cognate TCR discovery for cancer immunotherapy

基于液体活检的工具包，用于癌症免疫治疗的新抗原和同源 TCR 发现

基本信息

批准号：
10684704
负责人：
Wei Wei
金额：
$ 44.27万
依托单位：
INSTITUTE FOR SYSTEMS BIOLOGY
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：
2021-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684704
关键词：
Address Adoption Advanced Development Alleles Antigens Autologous Bar Codes Binding Biological Assay Biopsy Biopsy Specimen Blood Blood specimen Cancer Vaccines Cell Separation Cells Cellular immunotherapy Clinical Cytomegalovirus Data Diagnosis Disease Progression Ecosystem Engineering Evolution Exclusion Freezing Human Human Herpesvirus 4 Image Cytometry Immune Immunotherapy Kinetics Lesion Libraries Lymphocyte Malignant Neoplasms Medical center Molecular Profiling Monitor Mutation Neoplasm Circulating Cells Oncologist Operative Surgical Procedures Paraffin Embedding Pathologic Patients Peptide/MHC Complex Peripheral Peripheral Blood Lymphocyte Pharmacotherapy Population Procedures Reference Standards Resistance Resolution Sampling Specimen T cell clonality T-Cell Receptor Genes T-Lymphocyte T-cell receptor repertoire Time Tumor Immunity Tumor Tissue Tumor-Infiltrating Lymphocytes Validation WT1 gene Work anti-tumor immune response antigen-specific T cells cancer immunotherapy cellular transduction checkpoint therapy clinical translation driving force dynamical evolution immune checkpoint blockade immunogenic insight liquid biopsy melanoma minimally invasive nanoparticle neoantigen vaccine neoantigens neoplastic cell novel overtreatment personalized immunotherapy programs recruit response screening single molecule tool transcriptome tumor tumor exome

项目摘要

Project Summary/Abstract Neoantigens derived from tumor-specific mutations are a major driving force behind the current cancer immunotherapies. The interactions between neoantigens and antigen-specific T cells enable T cell recognition and tumor killing. Resolving neoantigens and antigen-reactive T cells normally requires fresh (or snap frozen) tumor materials from which the tumor tissue can be sequenced and tumor-infiltrating lymphocytes can be isolated and expanded. Unfortunately, the availability of fresh (or snap frozen) tumor tissue biopsies is a significant limiting factor for personalized immunotherapy. Sequencing quality of paraffin-embedded pathological specimen is often suboptimal for neoantigen discovery. Sequencing data of a small biopsy from a single tumor lesion may not be representative of the tumor's full clonal spectrum. More importantly, the molecular profile of tumors evolves dynamically over time. But repeated biopsy sampling is seldom feasible for patients with many cancers that require invasive biopsy procedures. Circulating tumor cells (CTCs) and match blood lymphocytes are good surrogates for neoantigen and cognate TCR discovery. They enable clinicians to repeatedly and non-invasively interrogate the mutational landscape and dynamic evolution of the anti-tumor immunity via serially collected blood samples. A major technical challenge here is to develop high-throughput, low sample volume, minimally invasive tools to resolve the neoantigen and cognate TCR dynamics and to match the TCR genes with specific neoantigens. We propose to develop a toolkit for liquid biopsy-based neoantigen and cognate TCR discovery through a strategic integration of a novel on-chip image cytometry platform and a highly modular nanoparticle-barcoded single-molecule peptide-MHC tetramer cell sorting assay. We will perform advanced development and rigorous validation of the toolkit in this proposed work. We will investigate the dynamic evolution of neoantigen and TCR repertoires during immune checkpoint blockade using serially collected blood samples from melanoma patients. Upon successful completion, it will deliver a simple and noninvasive approach for liquid biopsy-based neoantigen and cognate TCR discovery for patients whose surgical biopsies are not available or not attainable, with transformative potentials on personalized neoantigen vaccines and T-cell based immunotherapies. The neoantigen and cognate TCR dynamics will provide critical insights into the understanding of immunotherapy response and resistance.

项目总结/文摘