Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.
Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.
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DOI：
10.1158/1078-0432.ccr-09-0731
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发表时间：
2009-11-01
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影响因子：
--
通讯作者：
Jayson GC
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文献类型：
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作者：
O'Connor JP;Carano RA;Clamp AR;Ross J;Ho CC;Jackson A;Parker GJ;Rose CJ;Peale FV;Friesenhahn M;Mitchell CL;Watson Y;Roberts C;Hope L;Cheung S;Reslan HB;Go MA;Pacheco GJ;Wu X;Cao TC;Ross S;Buonaccorsi GA;Davies K;Hasan J;Thornton P;del Puerto O;Ferrara N;van Bruggen N;Jayson GC
关于抗 VEGF 疗法的直接治疗效果的起效、持续时间和程度，人们知之甚少。这些知识将有助于指导从实验室到临床的靶向治疗的合理开发，并优化在早期临床试验中量化肿瘤功能的成像技术的使用。使用离体显微 CT 和体内超声成像进行临床前研究，以表征经抗 VEGF 抗体 G6-31 处理的人 HM-7 结直肠异种移植模型中的肿瘤脉管系统。通过定量 MRI 对 10 名接受贝伐珠单抗治疗的转移性 CRC 患者进行临床评估。显微 CT 实验表明，G6-31 给药后 24-48 小时内灌注血管减少（p ≤ 0.005）。超声成像证实同一时间范围内肿瘤血容量减少（p = 0.048）。与临床前结果一致，在接受单剂量贝伐单抗后 48 小时内，在患者 CRC 转移中检测到增强分数和血浆体积分数降低，并持续整个治疗周期。这些效应之后，第 12 天，9/26 个肿瘤的水肿消退（p = 0.0023）和肿瘤缩小。这些数据表明，VEGF 特异性抑制可在一个治疗周期内诱导快速的结构和功能效应，并具有下游显着的抗肿瘤活性。这一发现对于结合生理成像的早期临床试验的设计具有重要意义。该研究展示了动物数据如何帮助解释临床成像数据，这是验证肿瘤结构和功能的图像生物标志物的重要一步。
Little is known concerning the onset, duration and magnitude of direct therapeutic effects of anti-VEGF therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early phase clinical trials. Pre-clinical studies were performed using ex vivo micro-CT and in-vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative MRI in ten patients with metastatic CRC treated with bevacizumab. Micro-CT experiments demonstrated reduction in perfused vessels within 24-48 hours of G6-31 drug administration (p ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (p = 0.048). Consistent with the pre-clinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient CRC metastases within 48 hours after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (p = 0.0023) and tumor shrinkage in 9/26 tumors at day 12. These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant anti-tumor activity within one cycle of therapy. This finding has important implications for the design of early phase clinical trials that incorporate physiological imaging. The study demonstrates how animal data help interpret clinical imaging data, an important step towards the validation of image biomarkers of tumor structure and function.