Delineating Functional Immunity via Image-Guided PET

摘要 最近出现的肿瘤靶向免疫治疗策略获得了积极和持久的结果 在诊所里然而，至少有一半的癌症患者仍然没有反应，尽管他们试图设计自己的 免疫系统攻击并摧毁肿瘤。迫切需要成像生物标志物， 指导免疫治疗，无论肿瘤特征或治疗方式如何。能够非侵入性地 并对T细胞浸润、抗肿瘤活性和肿瘤抑制因子的表达进行定量成像。 通过正电子发射断层扫描（PET）将迅速确定二级干预的目标 以改善结果。在我们的研究中，我们将探索18F标记的双抗体靶向干扰素-γ（IFN-γ）， 询问免疫监视信号轴。我们假设这种免疫效应物的成像 分子，CD 8+细胞毒性T细胞（CTL）和Th 1介导的反应的标志，将更好地预测治疗 结果优于单独的总CD 8+或CD 3 + T细胞成像。我们将进一步监测IFN-γ与 检查点分子PD-1及其配体PD-L1通过PET在诱导的无反应性微环境中。 已建立并充分表征的免疫活性neu（HER 2的大鼠同源物）转基因和 neu+ TUBO异种移植小鼠将用于使用HER 2/neu DNA疫苗的主动和被动治疗 和抗neu单克隆抗体。我们的第二个目标是探索PET的潜力 放射性示踪剂在neu+肿瘤携带多样性远系小鼠中的应用，重现了人类的遗传异质性。 将进行遗传分析以鉴定与T细胞浸润、IFN-γ表达和PD相关的基因座。 1/PD-L1上调。其目标是确定遗传标记，以预测患者对免疫治疗的易感性 并确定潜在的新目标进行干预或成像。最后，作为临床的进展， 应用中，我们将评估IFN-γ PET示踪剂的人类类似物对肿瘤组织切片通过 回顾性组织病理学审查。比较分析成像探针与对照的离体结合。 进行组织学评分。阳性结果将保证临床翻译，以供知情应用 治疗策略。总的来说，拟议的研究可能会满足以下迫切需要： 开发图像引导工具，以监测标志性癌症提示的免疫促进治疗 免疫疗法的突破

Abstract Recent emerging tumor-targeted immunotherapy strategies are met with positive and durable outcomes in the clinic. Yet, at least half of cancer patients remain non-responsive despite attempts to engineer their own immune system to attack and destroy the tumor. There is an urgent need for imaging biomarkers to universally guide immunotherapy, regardless of tumor characteristics or treatment modality. The ability to non-invasively and quantitatively image T cell infiltration, anti-tumor activity and expression of tumor suppressors within the tumor through positron emission tomography (PET) will expeditiously identify targets of secondary intervention to improve outcomes. In our proposed study, we will explore 18F-labeled diabody targeting interferon- (IFN-) to interrogate the immune surveillance-signaling axis. We hypothesize that imaging of this immune effector molecule, a hallmark of CD8+ cytotoxic T cell (CTL) and Th1-mediated response, will better predict therapeutic outcomes over total CD8+ or CD3+ T cell imaging alone. We will further monitor the relationship of IFN- with the checkpoint molecules PD-1 and its ligand PD-L1 through PET in an induced anergic microenvironment. The established and well-characterized immune competent neu (the rat homolog of HER2) transgenic and neu+ TUBO xenograft mice will be utilized for active and passive treatment using a HER2/neu DNA vaccine and an anti-neu monoclonal antibody, respectively. Our second aim seeks to examine the potential of our PET radiotracers in neu+ tumor-bearing diversity outbred mice, which recapitulate genetic heterogeneity in humans. Genetic analysis will be conducted to identify loci associated with T cell infiltration, IFN- expression and PD- 1/PD-L1 upregulation. The goal is to identify genetic markers to predict patient susceptibility to immunotherapy and identify potential novel targets for intervention or imaging. Finally, as a progression toward clinical application, we will evaluate the human analog of the IFN- PET tracer against tumor tissue sections via a retrospective histopathological review. A comparative analysis of ex vivo binding of the imaging probe against histological scores will be conducted. Positive findings will warrant clinical translation for informed application of therapeutic strategies. Taken together, the proposed study can potentially address the critical need to develop image-guided tools to monitor immune-facilitated treatment as prompted by landmark cancer immunotherapy breakthroughs.