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：
10581857
负责人：
Heather Marie Gibson
金额：
$ 57.87万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581857
关键词：
Address Adjuvant Chemotherapy Antibodies Autoimmune Diseases Binding Breast Cancer Model Breast Cancer Patient CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Chronic Clinical Cytotoxic T-Lymphocytes DNA Detection Development Dose Drug Kinetics Drug or chemical Tissue Distribution ERBB2 gene Environment Equilibrium Evaluation Event Exhibits Formulation Genetic Genomics Homologous Gene Human Image Immune Immune checkpoint inhibitor Immune system Immunity ImmunoPET Immunologic Monitoring Immunosuppressive Agents Immunotherapy In Situ In Vitro Inbred Mouse Inflammatory Interferon Type II Intervention Investigational New Drug Application Malignant Neoplasms Maps Measures Mediating Memory Methods Modality Modeling Monitor Monoclonal Antibodies Mus Neoadjuvant Therapy Oncology Outcome Outcome Assessment PD-1/PD-L1 PD-L1 blockade Passive Immunotherapy Patients Peripheral Persuasive Communication Population Positron-Emission Tomography Prediction of Response to Therapy Predictive Value of Tests Preparation Process Production Quantitative Trait Loci Radioactive Rationalization Rattus Recombinants Retrospective Studies Rodent Role SNP array Single Nucleotide Polymorphism Map Specificity T cell anergy T cell infiltration T-Lymphocyte Technology Testing Therapeutic Tissues Toxicology Tracer Translations Trastuzumab Treatment outcome Tumor Immunity Up-Regulation Vaccination Variant Visualization Xenograft procedure analog antibody-dependent cell cytotoxicity biomarker discovery cancer immunotherapy cancer type clinical decision-making clinical translation cytotoxic CD8 T cells dosimetry effector T cell exhaustion genetic linkage analysis image guided imaging biomarker immune activation immune checkpoint blockade immunoregulation improved mouse model novel overexpression pre-clinical predictive marker programmed cell death ligand 1 programmed cell death protein 1 radiotracer response restraint tool treatment strategy tumor tumor eradication tumor heterogeneity tumor microenvironment

项目摘要

Abstract Immunotherapy has made an enormous impact in the treatment of multiple types of cancer, however most patients fail to benefit and methods to monitor response are lacking. To bridge this gap, we have developed non-invasive positron emission tomography (PET) tracers to interrogate immune activity in the tumor microenvironment. Immune cell release of interferon-γ (IFN-γ) is a hallmark of CD8+ cytotoxic T cell (CTL) and Th1-mediated immune activity, both of which contribute to anti-tumor immunity. Our results thus far show that antibody-based immunoPET tracers targeting IFN-γ can detect anti-tumor immunity after administration of immunotherapy, which correlates to treatment outcomes in preclinical tumor models. The current proposal will advance these studies by examining the potential of IFN-γ PET as a pre-treatment predictor of immunotherapy response. We will utilize novel Collaborative Cross recombinant inbred mouse models developed during the course of this project, which exhibit a wide range of response rates to immune checkpoint inhibitors (ICI) due to select variants in their genetic background. These models mimic the diversity of the human population, yet limit tumor heterogeneity as a variable by utilizing genetically identical tumor lines, allowing us to focus on the role of host immunity. We find pre-existing intratumoral IFN-γ expression correlates to ICI outcomes in these models, and we will now test whether IFN-γ PET imaging prior to therapy is predictive of ICI response. Positive results will support the use of IFN-γ PET as part of the formulation of patient treatment strategy. In a necessary step for clinical translation, we will also prepare to submit an investigational new drug (IND) application. Dosimetry, stability studies, and toxicology will be performed. Collectively, the proposed studies will support the clinical use of IFN-γ PET to address critical unmet needs, including predictive biomarker discovery and treatment monitoring technology for cancer immunotherapy. While this proposal focuses on oncology, immune monitoring technologies may also have additional application in multiple inflammatory and autoimmune conditions.

抽象的免疫疗法对多种类型癌症的治疗产生了巨大影响，但是大多数患者无法受益，并且缺乏监测反应的方法。为了弥合这一差距，我们已经发展了非侵入性正电子发射断层扫描（PET）示踪剂以询问肿瘤中的免疫活性微环境。干扰素-γ（IFN-γ）的免疫细胞释放是CD8+细胞毒性T细胞（CTL）和 Th1介导的免疫反应性，两者都有助于抗肿瘤免疫。到目前为止，我们的结果表明靶向IFN-γ的基于抗体的免疫集示踪剂可以在给药后检测抗肿瘤免疫史地免疫疗法与临床前肿瘤模型中的治疗结果相关。当前的建议将通过检查IFN-γPET作为免疫疗法的预处理预测因子的潜力来提高这些研究回复。我们将利用新型的协作交叉重组近交小鼠模型在该项目的过程，该项目对免疫检查点抑制剂（ICI）表现出广泛的响应率在其遗传背景中选择变体。这些模型模仿了人口的多样性，但限制肿瘤异质性是通过利用遗传学相同的肿瘤线的变量，使我们能够关注宿主免疫。我们发现预先存在的肿瘤内IFN-γ表达与这些模型中的ICI结果相关，现在，我们将测试治疗之前的IFN-γPET成像是否可以预测ICI反应。积极的结果将支持使用IFN-γPET作为患者治疗策略公式的一部分。在必要的步骤中临床翻译，我们还将准备提交调查新药（IND）应用。剂量法，将进行稳定研究和毒理学。拟议的研究集体支持临床用途 IFN-γPET以满足关键的未满足需求，包括预测性生物标志物发现和治疗监测癌症免疫疗法的技术。虽然该提议着重于肿瘤学，但免疫监测技术也可能在多种炎症和自身免疫性条件下具有额外的应用。