[18F]4FN PET Imaging of Innate Immunity Activation During Immunotherapy-Induced Adverse Events

[18F]4FN PET 成像显示免疫治疗引起的不良事件期间先天免疫激活

基本信息

批准号：
10689251
负责人：
Sattva S Neelapu
金额：
$ 56.17万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689251
关键词：
Adverse event Autoimmunity Biochemical Biocompatible Materials Biological Markers Biology Biotechnology CAR T cell therapy Cancer Patient Cells Collagen Arthritis Cytometry Diet Disease Effector Cell Generations Goals Hematologic Neoplasms Hot Spot Image Immune Immunologic Monitoring Immunological Models Immunotherapy Infiltration Inflammation Inflammatory Innate Immune System Investigation Iron Kinetics Knowledge Macrophage Macrophage Colony-Stimulating Factor Mediating Metabolic syndrome Modeling Molecular Monitor Monoclonal Antibodies Myelogenous NADPH Oxidase Naphthols Natural Immunity Nature Neurotoxicity Syndromes Neutrophil Infiltration Nitrogen Organ Oxidants Oxidation-Reduction Oxygen Participant Pathway interactions Patients Peroxidases Positron-Emission Tomography Pre-Clinical Model Process Production Proteins Radiopharmaceuticals Reaction Reactive Oxygen Species Reagent Reporting Role Series Serum Serum Markers Sex Differences Signal Transduction Signaling Molecule Superoxides Therapeutic Tissue imaging Tissues Tumor Immunity Validation bioluminescence imaging checkpoint inhibition checkpoint therapy clinical imaging clinical practice diagnostic value experience humanized mouse immune activation immune checkpoint immune-related adverse events in vivo insight melanoma molecular imaging mouse model neurotoxicity neutrophil nonalcoholic steatohepatitis novel pre-clinical radiotracer recruit response side effect small molecule tumor whole body imaging

项目摘要

ABSTRACT While monoclonal antibodies inhibiting immune checkpoints (ICI) and CAR T-cell therapies have dramatically changed the therapeutic options for many cancer patients, up to 60% of patients will experience immune-related adverse events (irAE) depending on the tumor type and immunotherapy. Thus, many patients treated with immunotherapy will not see long term benefit and therefore only suffer potential side effects (and possibly hyper progression), and the importance of predicting and managing immunotherapy-related adverse events has already been identified as a critical gap in knowledge and clinical practice. Significantly, a common molecular node of integration between the various inflammatory mechanisms of irAE, particularly in the subacute setting, focuses on spurious activation of the innate immune system. Recently, we reported the synthesis and validation of 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical for the selective imaging of high energy oxygen and nitrogen radical species (RONS) by PET/CT. [18F]4FN provides a convenient reagent for rapid, quantitative whole-body imaging to identify and monitor inflammatory foci generated by NADPH oxidase-2 (NOX2) and myeloperoxidase (MPO) of the innate immune system and multi-organ inflammation, including immunotherapy-mediated irAE. Monitoring irAE by PET imaging is the long-term clinical imaging goal of our line of investigation. Near-term, we propose to investigate the role of activated innate immunity in vivo by combined molecular imaging and multiplexed analysis of tissues in mechanism-based pre-clinical murine models of irAE for which we can enhance our understanding of the activation dynamics of innate immunity and gain signals of efficacy.

抽象的而抑制免疫检查点（ICI）和CAR T细胞疗法的单克隆抗体具有大大改变了许多癌症患者的治疗选择，多达60％的患者会经历免疫相关的不良事件（IRAE）取决于肿瘤类型和免疫疗法。因此，许多患者通过免疫疗法治疗将不会看到长期的益处，因此只会遭受潜在的副作用（和可能是超级进展），以及预测和管理与免疫疗法相关的不良的重要性事件已经被确定为知识和临床实践中的关键差距。值得注意的是，很常见 IRAE的各种炎症机制之间的整合分子节点，特别是在亚急性中设置，专注于先天免疫系统的虚假激活。最近，我们报道了合成和 4- [18F]氟-1-萘酚（[18F] 4FN）的验证，这是一种新型的氧化还原式的放射性药物，用于选择性通过PET/CT对高能量氧和氮自由基物种（RON）的成像。 [18F] 4FN提供了方便的快速，定量的全身成像的试剂，以识别和监测NADPH产生的炎症灶先天免疫系统和多器官炎症的氧化酶-2（NOX2）和髓过氧化物酶（MPO），包括免疫疗法介导的IRAE。通过PET成像监视IRAE是长期的临床成像目标我们的调查线。近期，我们建议通过通过基于机制的临床前鼠模型中组织的分子成像和多路复用分析我们可以为此增强对先天免疫激活动态的理解并获得的IRAE 功效的信号。