Meng Boyu, Folaron Margaret R, Strawbridge Rendall R, Sadeghipour Negar, Samkoe Kimberley S, Tichauer Kenneth, Davis Scott C
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755.
Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616.
Theranostics. 2020 Sep 14;10(24):11230-11243. doi: 10.7150/thno.45273. eCollection 2020.
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. 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. 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; = 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. 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.
针对肿瘤异常受体谱的免疫肿瘤治疗策略在癌症治疗中日益重要。然而，评估受体可用性（RA）和药物-靶点结合情况（这是治疗效果的重要决定因素），对于当前的成像策略来说具有挑战性，这主要是因为成像剂在肿瘤中的非特异性摄取行为复杂。在此，我们评估一种旨在补偿非特异性摄取的定量无创成像方法——磁共振成像耦合双试剂荧光断层扫描（MRI-PAFT），是否能够在原位脑肿瘤模型中快速评估一剂抗表皮生长因子受体（EGFR）抗体治疗后表皮生长因子受体的可用性。本研究纳入了携带相对高表达EGFR的原位脑肿瘤异种移植瘤（U251）（N = 10）或未检测到人类EGFR的（9L）（N = 9）小鼠。对于每种肿瘤类型，小鼠要么接受一剂西妥昔单抗治疗，要么不接受治疗。所有动物均使用MRI-PAFT进行扫描，在给予双试剂后立即开始扫描，并使用基于模型的方法恢复RA值，该方法使用试剂摄取的整个动态序列，以及一种简化的“快照”方法，该方法仅需要在两个时间点进行摄取测量。对不同组和不同技术之间恢复的RA值进行评估。对每只动物的肿瘤标本进行苏木精-伊红（H&E）染色和免疫组织化学（IHC）染色，以确认肿瘤的存在和EGFR状态。在携带EGFR（+）肿瘤的动物中，观察到治疗组和未治疗组动物的RA值存在显著差异（RA分别为0.24±0.15和0.61±0.18，p = 0.027），曲线下面积-受试者操作特征（AUC-ROC）值为0.92。我们没有观察到携带EGFR（-）肿瘤的治疗组和未治疗组动物的RA值存在统计学显著差异（RA分别为0.18±0.19和0.27±0.21；p = 0.89；AUC-ROC = 0.55），也没有观察到治疗的EGFR（+）肿瘤与治疗和未治疗的EGFR（-）肿瘤之间存在差异。值得注意的是，快照双试剂策略在试剂给药后仅30分钟内就量化了药物-受体结合情况。单独检查靶向试剂显示，即使在试剂给药24小时后，也没有能力根据治疗或受体状态区分肿瘤。这项研究表明，一种无创成像策略能够快速量化治疗后受体的可用性，这种能力可用于临床前药物开发、患者分层和治疗监测。
