Serial Ultrasound to Detect Early Response to Immunotherapy in Metastatic RCC

项目摘要 我们建议进行一项试验性研究，以检测免疫治疗最早在开始后3周的反应。 治疗，使用多普勒超声和对比增强超声(CEUS)来测量 转移性肾细胞癌患者的肿瘤血管。快速检测生物标志物 对肾癌治疗的反应是迫切需要的，因为并不是所有的患者都对一线治疗有反应 CTLA-4免疫检查点抑制剂(Ipilimumab)联合抗PD-1免疫检查点抑制剂 (Nivolumab)。然而，所有患者都忍受着这种联合治疗的副作用(疲劳、自身免疫 肝炎/甲状腺炎/肺炎等)同时等待标准护理的计算机断层扫描(CT)成像。 目前，通过CT测量肿瘤直径的缩小来评估疗效需要12周，因为 治疗12周前肿瘤大小无明显变化。肾细胞癌治疗反应的快速检测 将最大限度地减少无效药物的使用，并允许患者停止无效的治疗，而只继续 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，可以检测到mRCC对治疗的早期反应。但这些都需要潜在的肾毒性碘对比剂 代理和对放射科的探视。我们已经开发出高度敏感的、非对比剂的血管 使用先进的能量多普勒超声成像，可在肿瘤科诊所的床边进行 影像血管直径小至1毫米。现在，我们建议使用先进的能量多普勒超声来 一项评估患者在接受常规肿瘤门诊期间肿瘤血管变化的试点研究 联合治疗，并与传统的能量多普勒和超声造影(CEUS)进行比较， 使用无肾毒性的微/纳米气泡造影剂)。我们假设肿瘤的变化 通过超声波测量血管，可以比肿瘤的变化更早地检测到对治疗的反应 直径。我们将招募30名肾细胞癌患者，在此之前接受多普勒超声和CEUS检查。 治疗后3周和6周联合应用伊普利姆单抗和尼伏卢单抗。我们的初步研究旨在 为了确定1)多普勒超声和/或CEU是否能最早在3周和/或6周后检测到变化 启动免疫治疗；2)如果超声检测到的变化与标准- 治疗12周后的护理CT扫描；3)哪个超声时间点(3周或6周)更好 预计12周内的结果。我们将使用超声成像来加速检测对 联合应用ipilimumab+nivolumab。如果成功，我们可以将我们的方法应用于更多的肿瘤和药物， 因为肿瘤血管的变化是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.