Serial Ultrasound to Detect Early Response to Immunotherapy in Metastatic RCC

项目摘要 我们建议进行一项试点研究，以检测免疫治疗后3周内的反应， 治疗，使用多普勒超声和对比增强超声（CEUS）来测量 转移性肾细胞癌（mRCC）患者的肿瘤血管分布。快速检测的生物标志物 对RCC治疗的反应是迫切需要的，因为并非所有患者都对一线治疗有反应， 联合CTLA-4免疫检查点抑制剂（伊匹单抗）+抗PD-1免疫检查点抑制剂 （纳武单抗）。然而，所有患者都忍受这种联合治疗的副作用（疲劳、自身免疫性 肝炎/甲状腺炎/肺炎等）同时等待标准护理计算机断层扫描（CT）成像。 目前，需要12周通过CT测量肿瘤直径的减小来评估反应， 肿瘤大小在12周治疗前没有显著变化。快速检测对RCC治疗的反应 将最大限度地减少无效药物的使用，并允许患者停止无效治疗， 有效的治疗。我们发现，基于成像的肿瘤血管测量，如灌注CT， 扫描，可以检测早期反应的治疗mRCC。但这些需要潜在的肾毒性碘造影剂 代理人和访问放射科。我们已经开发出了高灵敏度，非造影，血管 使用先进的能量多普勒超声成像，可以在肿瘤诊所的床边进行， 成像直径小至1 mm的血管。现在，我们建议使用先进的功率多普勒超声， 一项初步研究，旨在评估接受以下治疗的患者在常规肿瘤学门诊访视期间肿瘤血管分布的变化： 联合治疗，并将其与传统的能量多普勒和对比增强超声（CEUS， 使用非肾毒性的微泡/纳米泡造影剂）。我们假设肿瘤的变化 通过超声测量的血管分布可以比肿瘤变化更早地检测到对治疗的反应。 直径。我们将招募30例mRCC患者，在术前进行多普勒超声和CEUS评估， 治疗后以及在伊匹单抗和纳武单抗组合治疗3周和6周后。我们的试点研究旨在 以确定1）多普勒超声和/或CEUS是否可以在术后3周和/或6周检测到变化 启动免疫疗法; 2）如果通过超声检测到的变化与通过标准- 治疗12周后的出院CT扫描;以及3）哪个超声时间点（3周或6周）更好 预计12周的结果。我们将使用超声波成像来加速检测反应， 联合伊匹单抗+纳武单抗。如果成功，我们可以将我们的方法应用于其他肿瘤和药物， 因为肿瘤血管分布的变化是对大多数癌症治疗反应的关键机制。

Project Summary We propose a pilot study to detect response to immunotherapy as early as 3 weeks after initiating therapy, using Doppler ultrasound and contrast-enhanced ultrasound (CEUS) to measure changes in tumor vascularity in patients with metastatic renal cell carcinoma (mRCC). Biomarkers to rapidly detect response to RCC therapy are urgently needed, because not all patients respond to first-line treatment with combined CTLA-4 immune checkpoint inhibitor (ipilimumab) plus anti-PD-1 immune checkpoint inhibitor (nivolumab). Yet, all patients endure the side effects of this combination treatment (fatigue, autoimmune hepatitis/thyroiditis/pneumonitis etc.) while awaiting standard-of-care computed tomography (CT) imaging. Currently, 12 weeks is required to assess response by measuring decreases in tumor diameters with CT because tumor size does not significantly change before 12 weeks of therapy. Rapid detection of response to RCC therapy would minimize use of ineffective drugs and allow patients to discontinue ineffective therapies and continue only effective therapy. We have found that imaging-based measurements of tumor vascularity, such as perfusion CT scans, can detect early response to therapy in mRCC. But these require potentially nephrotoxic iodine contrast agents and visits to the radiology department. We have developed highly sensitive, non-contrast, vascular imaging using advanced power Doppler ultrasound that can be performed at bedside in the oncology clinic to image vessels as small as 1 mm in diameter. Now, we propose to use advanced power Doppler ultrasound for a pilot study to assess changes in tumor vascularity, during routine oncology clinic visits for patients receiving combined therapy, and compare it to conventional power Doppler and contrast-enhanced ultrasound (CEUS, using non-nephrotoxic micro-/nanobubble contrast agents). We hypothesize that changes in tumor vascularity, measured by ultrasound, can detect response to treatment earlier than changes in tumor diameters. We will enroll 30 patients with mRCC, to be evaluated with Doppler ultrasound and CEUS before treatment and after 3 weeks and 6 weeks of combined ipilimumab and nivolumab therapy. Our pilot study aims to determine if 1) Doppler ultrasound and/or CEUS can detect changes as early as 3 and/or 6 weeks after initiating immunotherapy; 2) if changes detected by ultrasound correlate with response measured by standard- of-care CT scan after 12 weeks of therapy; and 3) which ultrasound time point (3 weeks or 6 weeks) better anticipates 12-week results. We will use ultrasound imaging to accelerate detection of response to combined ipilimumab + nivolumab. If successful, we can apply our approach to additional tumors and drugs, as changes in tumor vascularity are a key mechanism of response to most cancer therapies.