Delineating Functional Immunity via Image-Guided PET

通过图像引导 PET 描绘功能性免疫

基本信息

批准号：
9751237
负责人：
Heather Marie Gibson
金额：
$ 54.97万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751237
关键词：
Address Binding Breast Cancer Model Breast Cancer Patient CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell physiology Cells Characteristics Chronic Clinic Clinical Cytotoxic T-Lymphocytes DNA DNA Vaccines Detection Development Dose Drug Kinetics Drug or chemical Tissue Distribution ERBB2 gene Engineering Environment Equilibrium Evaluation Event Genetic Genetic Heterogeneity Genetic Markers Genomics Goals Histologic Homologous Gene Human Image Imagery Immune Immune system Immunity Immunologic Monitoring Immunologic Surveillance Immunotherapy In Situ In Vitro Inflammatory Interferon-alpha Interferons Intervention Label Ligands Malignant Neoplasms Measures Mediating Memory Methods Modality Monitor Monoclonal Antibodies Mus Neoadjuvant Therapy Outcome PD-1/PD-L1 PDCD1LG1 gene Passive Immunotherapy Patient-Focused Outcomes Patients Peripheral Play Population Positron-Emission Tomography Predictive Value of Tests Predisposition Process Production Quantitative Trait Loci Radioactive Rattus Retrospective Studies Rodent Role SLEB2 gene Signal Transduction Single Nucleotide Polymorphism Specificity T cell anergy T-Lymphocyte Testing Therapeutic Time Tissues Tracer Transgenic Organisms Translations Trastuzumab Tumor Immunity Tumor Suppressor Proteins Tumor Tissue Tumor-infiltrating immune cells Up-Regulation Vaccination Xenograft procedure analog anti-tumor immune response antibody-dependent cell cytotoxicity cancer immunotherapy cellular imaging chemotherapy clinical application clinical translation comparative effector T cell exhaustion genetic analysis genetic linkage analysis image guided imaging biomarker imaging probe immune activation immune checkpoint blockade immunoregulation improved improved outcome mouse model non-invasive imaging novel overexpression pre-clinical predictive marker predictive test quantitative imaging radiotracer response therapy outcome tool tumor tumor microenvironment

项目摘要

Abstract Recent emerging tumor-targeted immunotherapy strategies are met with positive and durable outcomes in the clinic. Yet, at least half of cancer patients remain non-responsive despite attempts to engineer their own immune system to attack and destroy the tumor. There is an urgent need for imaging biomarkers to universally guide immunotherapy, regardless of tumor characteristics or treatment modality. The ability to non-invasively and quantitatively image T cell infiltration, anti-tumor activity and expression of tumor suppressors within the tumor through positron emission tomography (PET) will expeditiously identify targets of secondary intervention to improve outcomes. In our proposed study, we will explore 18F-labeled diabody targeting interferon- (IFN-) to interrogate the immune surveillance-signaling axis. We hypothesize that imaging of this immune effector molecule, a hallmark of CD8+ cytotoxic T cell (CTL) and Th1-mediated response, will better predict therapeutic outcomes over total CD8+ or CD3+ T cell imaging alone. We will further monitor the relationship of IFN- with the checkpoint molecules PD-1 and its ligand PD-L1 through PET in an induced anergic microenvironment. The established and well-characterized immune competent neu (the rat homolog of HER2) transgenic and neu+ TUBO xenograft mice will be utilized for active and passive treatment using a HER2/neu DNA vaccine and an anti-neu monoclonal antibody, respectively. Our second aim seeks to examine the potential of our PET radiotracers in neu+ tumor-bearing diversity outbred mice, which recapitulate genetic heterogeneity in humans. Genetic analysis will be conducted to identify loci associated with T cell infiltration, IFN- expression and PD- 1/PD-L1 upregulation. The goal is to identify genetic markers to predict patient susceptibility to immunotherapy and identify potential novel targets for intervention or imaging. Finally, as a progression toward clinical application, we will evaluate the human analog of the IFN- PET tracer against tumor tissue sections via a retrospective histopathological review. A comparative analysis of ex vivo binding of the imaging probe against histological scores will be conducted. Positive findings will warrant clinical translation for informed application of therapeutic strategies. Taken together, the proposed study can potentially address the critical need to develop image-guided tools to monitor immune-facilitated treatment as prompted by landmark cancer immunotherapy breakthroughs.

抽象的近期新兴肿瘤的免疫疗法策略具有积极和耐用的结果在诊所。然而，至少有一半的癌症患者仍然是无反应的目的地尝试来设计自己的免疫系统攻击和破坏肿瘤。迫切需要想象生物标志物普遍指导免疫疗法，无论肿瘤特征或治疗方式如何。非侵入性的能力和定量图像T细胞浸润，抗肿瘤活性和肿瘤补充剂的表达通过正电子发射断层扫描（PET）的肿瘤将迅速确定二次干预的靶标改善结果。在我们提出的研究中，我们将探索针对干扰的18F标记的透射透射型（IFN-）询问免疫监视信号轴。我们假设该免疫效应子的成像分子是CD8+细胞毒性T细胞（CTL）和Th1介导的反应的标志，将更好地预测治疗单独使用CD8+或CD3+ T细胞成像的结果。我们将进一步监视IFN-与检查点分子PD-1及其配体PD-L1通过PET在诱导的厌氧微环境中。已建立且特征良好的免疫能力NEU（HER2的大鼠同源物）转基因和 Neu+ Tubo Xenographichographographic小鼠将用于使用HER2/NEU DNA疫苗进行主动和被动治疗和抗NEU单克隆抗体。我们的第二个目标旨在检查宠物的潜力 NEU+含有肿瘤多样性的小鼠中的放射性示例，这些小鼠概括了人类的遗传异质性。将进行遗传分析，以确定与T细胞浸润，IFN-表达和PD-相关的局部分析 1/PD-L1上调。目的是确定遗传标记以预测患者对免疫疗法的敏感性并确定潜在的新型干预或成像目标。最后，作为临床的发展应用，我们将通过A评估IFN-PET示踪剂针对肿瘤组织的人类类似物回顾性组织病理学评论。对成像探针的离体结合的比较分析将进行组织学评分。积极的发现将需要临床翻译用于知情申请理论策略。综上所述，拟议的研究可以潜在地解决至关重要的需求开发图像引导的工具，以监测具有里程碑意义的癌症的可能性免疫疗法突破。