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.

抽象的最近新兴的肿瘤靶向免疫治疗策略取得了积极且持久的成果然而，在临床上，尽管尝试改造自己的癌症患者，但至少有一半的癌症患者仍然没有反应。免疫系统攻击和破坏肿瘤迫切需要普遍的成像生物标志物。指导免疫治疗，无论肿瘤特征或治疗方式如何。并对 T 细胞浸润、抗肿瘤活性和肿瘤抑制因子的表达进行定量成像通过正电子发射断层扫描（PET）对肿瘤进行诊断将迅速确定二次干预的目标在我们提出的研究中，我们将探索靶向干扰素- (IFN-) 的 18F 标记双抗体。我们捕获了该免疫效应器的成像。分子是 CD8+ 细胞毒性 T 细胞 (CTL) 和 Th1 介导反应的标志，将更好地预测治疗效果我们将进一步监测 IFN-γ 与单独的总 CD8+ 或 CD3+ T 细胞成像的结果。检查点分子 PD-1 及其配体 PD-L1 通过 PET 在诱导的无反应性微环境中进行检测。已建立且已充分表征的免疫能力 neu（HER2 的大鼠同源物）转基因和 neu+ TUBO 异种移植小鼠将用于使用 HER2/neu DNA 疫苗进行主动和被动治疗我们的第二个目标是检验我们的 PET 的潜力。 neu+肿瘤多样性远交小鼠中的放射性示踪剂，再现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-γ 表达和 PD-相关的基因座。 1/PD-L1 上调的目标是识别遗传标记来预测患者对免疫治疗的敏感性。并确定潜在的干预或成像新目标，作为临床的进展。应用程序中，我们将通过回顾性组织病理学评价成像探针的离体结合的比较分析。将进行组织学评分，以保证临床转化以供知情应用。综上所述，拟议的研究可能会满足以下迫切需要：开发图像引导工具来监测由标志性癌症引起的免疫促进治疗免疫疗法的突破。