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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.

摘要