[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

• 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
• 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

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.

摘要 虽然抑制免疫检查点（ICI）的单克隆抗体和CAR T细胞疗法已经被证明是有效的。 极大地改变了许多癌症患者的治疗选择，高达60%的患者将经历 免疫相关不良事件（irAE），取决于肿瘤类型和免疫治疗。因此，许多患者 用免疫疗法治疗不会看到长期的益处，因此只会遭受潜在的副作用（和 可能过度进展），以及预测和管理免疫治疗相关不良反应的重要性。 事件已经被确定为知识和临床实践的关键差距。值得注意的是，一个共同的 irAE的各种炎症机制之间整合的分子节点，特别是在亚急性 设置，侧重于先天免疫系统的虚假激活。最近，我们报道了合成和 验证4-[18F]氟-1-萘酚（[18F]4FN），一种新型的氧化还原调节放射性药物，用于选择性 通过PET/CT对高能氧和氮自由基物质（RONS）进行成像。[18F]4FN提供了一个方便的 用于快速、定量全身成像以识别和监测由NADPH产生的炎性病灶的试剂 氧化酶-2（NOX 2）和髓过氧化物酶（MPO）的先天免疫系统和多器官炎症， 包括免疫疗法介导的irAE。通过PET成像监测irAE是长期的临床成像目标 我们的调查线。近期，我们建议通过以下方法研究激活的先天免疫在体内的作用： 基于机制的临床前小鼠模型中组织的组合分子成像和多重分析 的irAE，我们可以提高我们的理解的激活动力学的先天免疫和增益 功效的信号。