Delineating Functional Immunity via Image-Guided PET

摘要 然而，免疫疗法在多种癌症的治疗中产生了巨大的影响。 大多数患者未能受益，缺乏监测反应的方法。为了弥合这一差距，我们开发了 无创正电子发射断层扫描(PET)示踪剂用于询问肿瘤的免疫活性 微环境。免疫细胞释放干扰素-γ(干扰素-γ)是CD8+细胞毒性T细胞的标志。 Th1介导的免疫活性，两者都有助于抗肿瘤免疫。到目前为止，我们的结果表明 针对干扰素-γ的抗体免疫正电子发射体层析示踪剂可检测给药后的抗肿瘤免疫 免疫治疗，这与临床前肿瘤模型的治疗结果相关。目前的提案将 通过检测干扰素-γ正电子发射计算机断层扫描作为免疫治疗前预测指标的潜力来推进这些研究 回应。我们将利用新的合作杂交重组近交系小鼠模型 该项目的进程，表现出对免疫检查点抑制剂(ICI)的广泛应答率，原因是 选择遗传背景中的变异。这些模型模拟了人类种群的多样性，但限制了 通过利用基因相同的肿瘤株，将肿瘤的异质性作为一个变量，使我们能够专注于 宿主豁免权。我们发现，在这些模型中，预先存在的肿瘤内干扰素-γ的表达与脑梗塞的预后相关。 我们现在将测试治疗前的干扰素-γ正电子发射计算机断层扫描是否可以预测脑梗塞的反应。积极的结果 将支持使用干扰素-γ正电子发射计算机断层扫描作为制定患者治疗策略的一部分。在必要的步骤中 除了临床翻译，我们还将准备提交研究新药(IND)申请。剂量学， 将进行稳定性研究和毒理学研究。总的来说，拟议的研究将支持临床应用 干扰素-γ正电子发射计算机断层扫描以解决关键的未得到满足的需求，包括预测性生物标记物发现和治疗监测 癌症免疫治疗技术。虽然这项提案的重点是肿瘤学，但免疫监测 这些技术还可能在多种炎症和自身免疫条件下有更多的应用。

Abstract Immunotherapy has made an enormous impact in the treatment of multiple types of cancer, however most patients fail to benefit and methods to monitor response are lacking. To bridge this gap, we have developed non-invasive positron emission tomography (PET) tracers to interrogate immune activity in the tumor microenvironment. Immune cell release of interferon-γ (IFN-γ) is a hallmark of CD8+ cytotoxic T cell (CTL) and Th1-mediated immune activity, both of which contribute to anti-tumor immunity. Our results thus far show that antibody-based immunoPET tracers targeting IFN-γ can detect anti-tumor immunity after administration of immunotherapy, which correlates to treatment outcomes in preclinical tumor models. The current proposal will advance these studies by examining the potential of IFN-γ PET as a pre-treatment predictor of immunotherapy response. We will utilize novel Collaborative Cross recombinant inbred mouse models developed during the course of this project, which exhibit a wide range of response rates to immune checkpoint inhibitors (ICI) due to select variants in their genetic background. These models mimic the diversity of the human population, yet limit tumor heterogeneity as a variable by utilizing genetically identical tumor lines, allowing us to focus on the role of host immunity. We find pre-existing intratumoral IFN-γ expression correlates to ICI outcomes in these models, and we will now test whether IFN-γ PET imaging prior to therapy is predictive of ICI response. Positive results will support the use of IFN-γ PET as part of the formulation of patient treatment strategy. In a necessary step for clinical translation, we will also prepare to submit an investigational new drug (IND) application. Dosimetry, stability studies, and toxicology will be performed. Collectively, the proposed studies will support the clinical use of IFN-γ PET to address critical unmet needs, including predictive biomarker discovery and treatment monitoring technology for cancer immunotherapy. While this proposal focuses on oncology, immune monitoring technologies may also have additional application in multiple inflammatory and autoimmune conditions.