Delineating Functional Immunity via Image-Guided PET

通过图像引导 PET 描绘功能性免疫

• 批准号: 10224119
• 负责人: Heather Marie Gibson
• 金额: $ 53.99万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10224119
• 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; Immune; Immune system; Immunity; Immunocompetent; Immunologic Monitoring; Immunologic Surveillance; Immunosuppressive Agents; 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; PD-L1 blockade; 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; SNP array; Signal Transduction; 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; Visualization; Xenograft procedure; analog; anti-tumor immune response; antibody-dependent cell cytotoxicity; cancer immunotherapy; cellular imaging; chemotherapy; clinical application; clinical translation; comparative; cytotoxic CD8 T cells; 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; programmed cell death ligand 1; programmed cell death protein 1; quantitative imaging; radiotracer; response; therapy outcome; tool; tumor; tumor microenvironment

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.

摘要 最近出现的肿瘤靶向免疫治疗策略取得了积极和持久的结果 在诊所里。然而，尽管试图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 免疫系统攻击并摧毁肿瘤。迫切需要对生物标记物进行成像，以普遍 指导免疫治疗，不考虑肿瘤特征或治疗方式。非侵入性的能力 并定量成像T细胞浸润、抗肿瘤活性和肿瘤抑制因子在体内的表达 通过正电子发射断层扫描(PET)可以快速确定二次介入的靶点 以改善结果。在我们计划的研究中，我们将探索18F标记的干扰素-(干扰素-) 询问免疫监视信号轴。我们假设这种免疫效应器的成像 分子，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 结果超过总CD8+或CD3+T细胞单独成像。我们将进一步监测干扰素-与 在诱导的无能微环境中，检查点分子PD-1及其配体PD-L1通过PET。 已建立和特征良好的免疫活性neu(HER2的大鼠同源物)转基因和 Neu+Tubo异种移植小鼠将使用HER2/neu DNA疫苗进行主动和被动治疗 和抗neu单抗。我们的第二个目标是检查我们的PET的潜力 Neu+肿瘤杂交种小鼠的放射性示踪剂，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、干扰素-表达和帕金森病相关的基因座。 1/PD-L1上调。其目标是确定预测患者对免疫治疗易感性的遗传标记。 并确定用于干预或成像的潜在新目标。最后，随着临床的进展 应用，我们将评估干扰素-PET示踪剂对肿瘤组织切片的人类类似物通过 组织病理学回顾。成像探针与抗癌药物体外结合的比较分析 将进行组织学评分。阳性结果将保证临床翻译以供知情应用 治疗策略。综上所述，拟议的研究可能会解决以下关键需求 开发图像引导工具，以监控里程碑式癌症引发的免疫促进治疗 免疫治疗取得突破。