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

摘要 而抑制免疫检查点(ICI)的单抗能够恢复抗肿瘤免疫 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ICI。因此，大多数人 接受ICI治疗的患者不会看到长期的好处，因此只会遭受潜在的副作用(并且可能 超级进展)，预测和管理ICI相关不良事件的重要性已经被 被确定为知识和临床实践中的关键差距。值得注意的是，一个常见的分子节点 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， 重点是对先天免疫系统的虚假激活。在这方面，我们最近报道了 新型氧化还原调谐放射性药物4-[18F]-1-萘酚([18F]4FN)的发现与验证 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情况 参与先天免疫。这种新型的PET放射性药物可能为快速、 自由基介导性炎性灶的全身成像和定量无创监测 在ICI介导的IRAE过程中被先天免疫系统激活。PET显像监测IRAE是一项长期的临床工作 这条线调查的成像目标。对于此R21提案，我们建议1)推动代理商进入First in-in- 在MDACC患者中进行相关人群的人体剂量学和安全性研究，以及2)收益 初步的疗效信号。如果成功，这种新的试剂可能会增加PET的临床精确度。 医药。

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.