Predicting response to radioimmunotherapy from the tumor microenvironment of colorectal carcinomas
Predicting response to radioimmunotherapy from the tumor microenvironment of colorectal carcinomas
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DOI：
10.1158/0008-5472.can-07-2967
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发表时间：
2007-12-15
期刊：
影响因子：
11.2
通讯作者：
Pedley, R. Barbara
中科院分区：
文献类型：
--
作者：
El Emir, Ethaar;Qureshi, Uzma;Pedley, R. Barbara
实体瘤具有异质性的病理生理机制，这直接影响抗体靶向治疗。在这里，我们通过比较放射性标记抗体和荧光标记抗体(A5B7抗癌胚抗原抗体和非特异性对照)静脉注射后的大体生物分布、微观分布和治疗效果，来考虑选定的肿瘤参数对放射免疫治疗的影响。在MF1裸鼠体内注射两种不同的人结直肠移植瘤。LS174T具有中/低分化，而SW1222具有分化良好的腺体结构。生物分布研究(1.8MBq(131)I标记的A5B7，每组4只小鼠)显示，两种模型在48it时的肉眼肿瘤摄取相似(每克注射剂量分别为25.1%和24.0%)。然而，在治疗研究中(每组6只小鼠)，LS174T需要增加3倍的剂量(18MBq对6MBq)才能等同于SW1222的生长抑制(分别类似于55天和类似60天)。为了研究这种差异的基础，使用高分辨率多荧光显微镜研究了抗体定位与肿瘤参数(5min、1h和24h，每个时间点4只小鼠)的关系。三维微血管腐蚀铸型和透射电子显微镜显示异种移植物之间存在进一步的结构差异。不同模型之间的血管供应、整体抗原分布和肿瘤结构差异很大，这是抗体定位和随后的治疗效果的主要差异的主要原因。研究表明，需要对治疗和肿瘤微环境进行多参数、高分辨率成像，以了解复杂的抗体-肿瘤相互作用，并确定哪些肿瘤区域正在成功治疗。这将为单一药物和联合药物的优化临床试验的设计提供信息，并帮助个体患者选择抗体靶向治疗。
Solid tumors have a heterogeneous pathophysiology, which directly affects antibody-targeted therapies. Here, we consider the influence of selected tumor parameters on radioimmunotherapy, by comparing the gross biodistribution, microdistribution, and therapeutic efficacy of either radiolabeled or fluorescently labeled antibodies (A5B7 anti-carcinoembryonic antigen antibody and a nonspecific control) after i.v. injection in two contrasting human colorectal xenografts in MF1 nude mice. The LS174T is moderately/poorly differentiated, whereas SW1222 has a well-differentiated glandular structure. Biodistribution studies (1.8 MBq (131) I-labeled A5B7, four mice per group) showed similar gross tumor uptake at 48 It in the two models (25.1% and 24.0% injected dose per gram, respectively). However, in therapy studies (six mice per group), LS174T required a 3-fold increase in dose (18 versus 6 MBq) to equal SW1222 growth inhibition (similar to 55 versus similar to 60 days, respectively). To investigate the basis of this discrepancy, high-resolution multifluorescence microscopy was used to study antibody localization in relation to tumor parameters (5 min, I and 24 h, four mice per time point). Three-dimensional microvascular corrosion casting and transmission electron microscopy showed further structural differences between xenografts. Vascular supply, overall antigen distribution, and tumor structure varied greatly between models, and were principally responsible for major differences in antibody localization and subsequent therapeutic efficacy. The study shows that multiparameter, high-resolution imaging of both therapeutic and tumor microenvironment is required to comprehend complex antibody-tumor interactions, and to determine which tumor regions are being successfully treated. This will inform the design of optimized clinical trials of single and combined agents, and aid individual patient selection for antibody-targeted therapies.