First-in-Human Imaging of Innate Immunity Activation with a Redox-Tuned PET Reporter

使用氧化还原调谐 PET 报告基因首次对人体进行先天免疫激活成像

• 批准号: 10577531
• 负责人: David Piwnica-Worms
• 金额: $ 22.72万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577531
• 关键词: Adverse event; Binding; Biochemical; Biological; Biology; Biotechnology; Cancer Patient; Cells; Chemistry; Clinical; Data; Disease; Female; Generations; Goals; Hot Spot; Human; Image; Immune; Immunologic Monitoring; Immunologic Surveillance; Immunological Diagnosis; Infiltration; Inflammatory; Injections; Innate Immune System; Institutional Review Boards; Intervention; Investigation; Iron; Knowledge; Laboratories; Macrophage; Mediating; Molecular; Monoclonal Antibodies; Mus; Myelogenous; NADPH Oxidase; Naphthols; Natural Immunity; Nature; Nitrogen; Organ; Oxidants; Oxidation-Reduction; Participant; Pathway interactions; Patients; Peroxidases; Phase; Phase 0/1 Trial; Positron-Emission Tomography; Process; Production; Proteins; Radiopharmaceuticals; Reaction; Reactive Oxygen Species; Reagent; Recording of previous events; Reporter; Reporting; Safety; Series; Serum; Signal Transduction; Signaling Molecule; Superoxides; Therapeutic; Time; Tissues; Tracer; Tumor Immunity; University of Texas M D Anderson Cancer Center; Validation; X-Ray Computed Tomography; checkpoint inhibition; clinical imaging; clinical practice; cohort; diagnostic value; dosimetry; experience; first-in-human; human imaging; imaging study; immune checkpoint; immune-related adverse events; in vivo; interest; liver inflammation; male; neutrophil; novel; patient population; precision medicine; primary endpoint; prospective; radiotracer; safety study; side effect; small molecule; tumor; whole body imaging

ABSTRACT While monoclonal antibodies inhibiting immune checkpoints (ICI) are able to restore anti-tumor immunity and 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 ICI. Thus, the majority of patients treated with ICI will not see long term benefit and therefore only suffer potential side effects (and possibly hyper progression), and the importance of predicting and managing ICI-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 imaging setting, focuses on the spurious activation of the innate immune system. In this regard, we recently reported the discovery and validation of 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical for selective imaging of highly oxidizing radicals by PET/CT, thus enabling interrogation of activation of key cells participating in innate immunity. This novel PET radiopharmaceutical may provide a convenient reagent for rapid, whole-body imaging and quantitative non-invasive surveillance of radical-mediated inflammatory foci generated by the innate immune system during ICI-mediated irAE. Monitoring irAE by PET imaging is the long-term clinical imaging goal of this line of investigation. For this R21 proposal, we propose to 1) drive the agent into first-in- human dosimetry and safety studies in a relevant population of patients at MDACC with irAE, and 2) gain preliminary signals of efficacy. If successful, this novel agent may increase the clinical utility of PET in precision medicine.

摘要 而抑制免疫检查点（ICI）的单克隆抗体能够恢复抗肿瘤免疫 并极大地改变了许多癌症患者的治疗选择，高达60%的患者将 根据肿瘤类型和ICI，发生免疫相关不良事件（irAE）。因此，大多数 用ICI治疗的患者不会看到长期益处，因此仅遭受潜在的副作用（并且可能 高进展），预测和管理ICI相关不良事件的重要性已经被 被认为是知识和临床实践中的关键差距。值得注意的是，一个共同的分子节点， irAE的各种炎症机制之间的整合，特别是在亚急性成像环境中， 专注于先天免疫系统的虚假激活。在这方面，我们最近报道了 4-[18F]氟-1-萘酚（[18F]4FN）的发现和验证，这是一种新型的氧化还原调节放射性药物， 通过PET/CT对高氧化性自由基进行选择性成像，从而能够询问关键细胞的激活情况 参与先天免疫。这种新型PET放射性药物可以提供一种方便的试剂， 全身成像和定量非侵入性监测产生的自由基介导的炎症灶 在ICI介导的irAE期间由先天免疫系统引起。通过PET成像监测irAE是长期的临床 这条调查线的成像目标。对于这个R21提案，我们建议1）将代理驱动为先进的， 在MDACC irAE患者相关人群中进行的人体剂量测定和安全性研究，以及2）获得 疗效的初步信号。如果成功的话，这种新的药物可能会增加PET的临床实用性， 药