Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers.
Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers.
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DOI：
10.1158/1078-0432.ccr-19-3717
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发表时间：
2020-06-01
影响因子：
11.5
通讯作者：
Rosenthal, Eben L.
中科院分区：
文献类型：
--
作者：
Lu, Guolan;Fakurnejad, Shayan;Martin, Brock A.;van den Berg, Nynke S.;van Keulen, Stan;Nishio, Naoki;Zhu, Ashley J.;Chirita, Stefania U.;Zhou, Quan;Gao, Rebecca W.;Kong, Christina S.;Fischbein, Nancy;Penta, Mrudula;Colevas, Alexander D.;Rosenthal, Eben L.
基于抗体的治疗剂的功效取决于药物成功递送到实体瘤中，因此存在测量肿瘤内抗体分布的临床需要。本研究旨在开发和验证一种成像和计算平台，以在临床研究中直接量化和预测抗体递送到人类头颈癌中。24名患者接受了近红外（NIR）荧光标记治疗性抗体的全身输注，随后进行了肿瘤切除手术。开发了一个计算平台来量化肿瘤内抗体分布的异质性程度。使用单变量和多变量回归分析来选择对抗体递送最具预测性的肿瘤生物学因素。提取来自预处理磁共振成像（MRI）的定量图像特征并与抗体递送的荧光成像相关联。该研究不仅证实了与许多临床前报告一致的异质性肿瘤内抗体分布，而且还量化了抗体递送的患者间、肿瘤间和肿瘤内异质性的程度。本研究证明了肿瘤大小对肿瘤内抗体积累的强预测价值及其对原发性肿瘤和淋巴结转移中抗体分布的显著影响。此外，本研究确立了使用对比增强MRI预测抗体递送的可行性。这项研究提供了一个临床上可翻译的平台来测量抗体递送到实体瘤中，并产生了对临床相关抗体肿瘤渗透的有价值的见解，这对选择适合抗体治疗的患者和设计更有效的给药策略具有重要意义。
The efficacy of antibody-based therapeutics depends on successful drug delivery into solid tumors, therefore there is a clinical need to measure intratumoral antibody distribution. This study aims to develop and validate an imaging and computation platform to directly quantify and predict antibody delivery into human head and neck cancers in a clinical study. Twenty-four patients received systemic infusion of a near-infrared (NIR) fluorescence-labeled therapeutic antibody followed by surgical tumor resection. A computational platform was developed to quantify the extent of heterogeneity of intratumoral antibody distribution. Both univariate and multivariate regression analysis were used to select the most predictive tumor biological factors for antibody delivery. Quantitative image features from the pre-treatment magnetic resonance imaging (MRI) were extracted and correlated with fluorescence imaging of antibody delivery. This study not only confirmed heterogeneous intratumoral antibody distribution in line with many preclinical reports, but also quantified the extent of inter-patient, inter-tumor, and intra-tumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both primary tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery. This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies.