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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的而抑制免疫检查点（ICI）的单克隆抗体能够恢复抗肿瘤免疫力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，会经历免疫相关不良事件 (irAE)。因此，大多数使用 ICI 治疗的患者不会看到长期获益，因此只会遭受潜在的副作用（并且可能超进展），预测和管理 ICI 相关不良事件的重要性已经得到了重视被认为是知识和临床实践中的一个关键差距。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，重点关注先天免疫系统的虚假激活。对此，我们近日报道了 4-[18F]氟-1-萘酚 ([18F]4FN) 的发现和验证，一种新型氧化还原调谐放射性药物通过 PET/CT 对高氧化自由基进行选择性成像，从而能够询问关键细胞的激活参与先天免疫。这种新型 PET 放射性药物可以提供一种方便的试剂，用于快速、对自由基介导的炎症灶进行全身成像和定量无创监测在 ICI 介导的 irAE 过程中，由先天免疫系统产生。通过 PET 成像监测 irAE 是长期的临床治疗该研究线的成像目标。对于这个 R21 提案，我们建议 1) 推动智能体进入先入为主的状态在 MDACC 的相关患者群体中进行人体剂量测定和安全性研究，其中包括 irAE，以及 2) 增益初步的功效信号。如果成功，这种新型药物可能会提高 PET 在精确度方面的临床应用药品。