Immuno-oncological treatment strategies that target abnormal receptor profiles of tumors are an increasingly important feature of cancer therapy. Yet, assessing receptor availability (RA) and drug-target engagement, important determinants of therapeutic efficacy, is challenging with current imaging strategies, largely due to the complex nonspecific uptake behavior of imaging agents in tumors. Herein, we evaluate whether a quantitative noninvasive imaging approach designed to compensate for nonspecific uptake, MRI-coupled paired-agent fluorescence tomography (MRI-PAFT), is capable of rapidly assessing the availability of epidermal growth factor receptor (EGFR) in response to one dose of anti-EGFR antibody therapy in orthotopic brain tumor models./nMethods: Mice bearing orthotopic brain tumor xenografts with relatively high EGFR expression (U251) (N=10) or undetectable human EGFR (9L) (N=9) were considered in this study. For each tumor type, mice were either treated with one dose of cetuximab, or remained untreated. All animals were scanned using MRI-PAFT, which commenced immediately after paired-agent administration, and values of RA were recovered using a model-based approach, which uses the entire dynamic sequence of agent uptake, as well as a simplified “snapshot” approach which requires uptake measurements at only two time points. Recovered values of RA were evaluated between groups and techniques. Hematoxylin & eosin (H&E) and immunohistochemical (IHC) staining was performed on tumor specimens from every animal to confirm tumor presence and EGFR status./nResults: In animals bearing EGFR(+) tumors, a significant difference in RA values between treated and untreated animals was observed (RA = 0.24 ± 0.15 and 0.61 ± 0.18, respectively, p=0.027), with an area under the curve - receiver operating characteristic (AUC-ROC) value of 0.92. We did not observe a statistically significant difference in RA values between treated and untreated animals bearing EGFR(-) tumors (RA = 0.18 ± 0.19 and 0.27 ± 0.21, respectively; p = 0.89; AUC-ROC = 0.55), nor did we observe a difference between treated EGFR(+) tumors compared to treated and untreated EGFR(-) tumors. Notably, the snapshot paired-agent strategy quantified drug-receptor engagement within just 30 minutes of agent administration. Examination of the targeted agent alone showed no capacity to distinguish tumors either by treatment or receptor status, even 24h after agent administration./nConclusions: This study demonstrated that a noninvasive imaging strategy enables rapid quantification of receptor availability in response to therapy, a capability that could be leveraged in preclinical drug development, patient stratification, and treatment monitoring.

中文翻译：

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使用配对剂荧光层析成像技术对治疗过程中靶标可用性进行无创量化

针对肿瘤的异常受体特征的免疫肿瘤治疗策略是癌症治疗中越来越重要的特征。然而，目前的成像策略对评估受体有效性（RA）和药物靶点参与（治疗效果的重要决定因素）提出了挑战，这主要是由于成像剂在肿瘤中的复杂非特异性摄取行为所致。本文中，我们评估了一种旨在补偿非特异性摄取的定量无创成像方法，即MRI耦合配对剂荧光层析成像（MRI-PAFT），该方法能够快速评估表皮生长因子受体（EGFR）的响应剂量在原位脑肿瘤models./n抗EGFR抗体治疗的方法：在这项研究中考虑了具有相对较高的EGFR表达（U251）（N = 10）或无法检测到的人EGFR（9L）（N = 9）的原位脑肿瘤异种移植小鼠。对于每种肿瘤类型，用一剂西妥昔单抗治疗小鼠，或者不予治疗。使用MRI-PAFT对所有动物进行扫描，该过程在配对药物给药后立即开始，并且使用基于模型的方法恢复了RA值，该方法使用了药物吸收的整个动态序列以及简化的“快照”方法仅需要在两个时间点进行吸收测量。在组和技术之间评估RA的恢复值。对每只动物的肿瘤标本进行苏木精和曙红（H＆E）和免疫组化（IHC）染色，以确认肿瘤的存在和EGFR状态。在患有EGFR（+）肿瘤的动物中，观察到治疗和未治疗的动物之间的RA值存在显着差异（分别为RA = 0.24±0.15和0.61±0.18，p = 0.027），曲线下的面积-受体工作特征（AUC-ROC）值为0.92。我们没有观察到治疗和未治疗的患有EGFR（-）肿瘤的动物之间的RA值在统计学上有显着差异（分别为RA = 0.18±0.19和0.27±0.21；p= 0.89; AUC-ROC = 0.55），我们也未观察到与未治疗和未治疗的EGFR（-）肿瘤相比，所治疗的EGFR（+）肿瘤之间存在差异。值得注意的是，快照配对代理策略仅在代理管理的30分钟内即可量化药物受体的参与度。结论：这项研究表明，无创成像策略能够快速量化受体对治疗的反应，这是一项无创的成像策略，能够通过治疗或受体状态对肿瘤进行区分，即使是在给药后24小时。可以在临床前药物开发，患者分层和治疗监测中加以利用。