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：
10272350
负责人：
Wei Wei
金额：
$ 46.29万
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/10272350
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 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-Derived Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Validation WT1 gene Work anti-tumor immune response antigen-specific T cells base cancer immunotherapy cellular transduction checkpoint therapy clinically translatable 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.

项目概要/摘要源自肿瘤特异性突变的新抗原是当前癌症背后的主要驱动力免疫疗法。新抗原和抗原特异性 T 细胞之间的相互作用使 T 细胞能够识别和肿瘤杀灭。解析新抗原和抗原反应性 T 细胞通常需要新鲜（或速冻）可以对肿瘤组织进行测序并可以分离肿瘤浸润淋巴细胞的肿瘤材料并扩大。不幸的是，新鲜（或速冻）肿瘤组织活检的可用性是一个重要的因素。个性化免疫治疗的限制因素。石蜡包埋病理标本测序质量对于新抗原的发现来说通常不是最佳的。来自单个肿瘤病灶的小活检的测序数据可能不能代表肿瘤的完整克隆谱。更重要的是，肿瘤的分子谱随着时间的推移动态演变。但对于患有多种癌症的患者来说，重复活检取样很少可行需要侵入性活检程序。循环肿瘤细胞 (CTC) 和匹配血液淋巴细胞是新抗原和同源物的良好替代物 TCR 发现。它们使临床医生能够反复、非侵入性地询问突变情况以及通过连续收集的血液样本抗肿瘤免疫力的动态进化。一项重大技术这里的挑战是开发高通量、低样本量、微创工具来解决新抗原和同源 TCR 动力学，并将 TCR 基因与特定新抗原相匹配。我们建议通过战略整合开发基于液体活检的新抗原和同源 TCR 发现工具包新型片上图像细胞计数平台和高度模块化的纳米颗粒条形码单分子肽-MHC 四聚体细胞分选测定。我们将进行先进的开发和严格的验证这项拟议工作中的工具包。我们将研究新抗原和 TCR 库的动态演化。使用从黑色素瘤患者连续采集的血液样本进行免疫检查点封锁。成功后完成后，它将为基于液体活检的新抗原和同源物提供一种简单且无创的方法针对无法或无法进行手术活检的患者进行 TCR 发现，并具有变革性个性化新抗原疫苗和基于 T 细胞的免疫疗法的潜力。新抗原和同源 TCR 动力学将为理解免疫治疗反应和耐药性提供重要见解。