Serial Ultrasound to Detect Early Response to Immunotherapy in Metastatic RCC

连续超声检测转移性肾细胞癌免疫治疗的早期反应

• 批准号: 10589070
• 负责人: Jeremy Dahl
• 金额: $ 21.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589070
• 关键词: Acceleration; Angiogenesis Inhibitors; Angiopoietins; Autoantibodies; Autoimmune Hepatitis; Biological Markers; Blood; Blood Vessels; Blood flow; CTLA4 gene; Clinic; Clinic Visits; Clinical; Combined Modality Therapy; Contrast Media; Detection; Diameter; Doppler Ultrasound; Early Diagnosis; Early treatment; Eligibility Determination; Enrollment; Erythrocytes; Excision; Exposure to; Fatigue; Hashimoto Disease; Hepatitis; Image; Imaging Techniques; Immune checkpoint inhibitor; Immune system; Immunotherapy; Individual; Infiltration; Iodine; Ionizing radiation; Kidney; Lead; Malignant Neoplasms; Measurement; Measures; Metastatic Renal Cell Cancer; Modality; Morphologic artifacts; Motion; Nivolumab; Noise; Oncology; Patients; Perfusion; Pharmaceutical Preparations; Pilot Projects; Porosity; Prediction of Response to Therapy; Primary Lesion; Pulmonary Inflammation; Radiology Specialty; Renal Cell Carcinoma; Renal carcinoma; Resistance; Scanning; Signal Transduction; T-Lymphocyte; Thyroiditis; Time; Treatment Side Effects; Tumor Burden; Tumor Suppressor Proteins; Ultrasonography; Visit; X-Ray Computed Tomography; angiogenesis; anti-CTLA4; anti-PD-1; cancer therapy; checkpoint inhibition; checkpoint therapy; contrast enhanced; effective therapy; ineffective therapies; innovation; ipilimumab; kidney dysfunction; nanobubble; nephrotoxicity; predicting response; prevent; quantitative imaging; rapid detection; response; side effect; standard measure; standard of care; treatment response; tumor; ultrasound

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.

项目概要 我们建议开展一项试点研究，最早在开始后 3 周内检测免疫治疗的反应 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 迫切需要了解 RCC 治疗的反应，因为并非所有患者都对一线治疗有反应 CTLA-4免疫检查点抑制剂（伊匹单抗）联合抗PD-1免疫检查点抑制剂 （纳武利尤单抗）。然而，所有患者都会忍受这种联合治疗的副作用（疲劳、自身免疫性疾病） 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 周才能通过 CT 测量肿瘤直径的减小来评估疗效，因为 治疗 12 周前，肿瘤大小没有显着变化。快速检测 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的治疗并仅继续 有效的治疗。我们发现基于成像的肿瘤血管分布测量，例如灌注 CT 扫描，可以检测 mRCC 治疗的早期反应。但这些需要潜在肾毒性的碘造影剂 代理和访问放射科。我们开发了高灵敏度、非造影剂、血管 使用先进的能量多普勒超声进行成像，可以在肿瘤诊所的床边进行 成像血管直径小至 1 毫米。现在，我们建议使用先进的能量多普勒超声 一项试点研究，旨在评估接受治疗的患者在常规肿瘤门诊就诊期间肿瘤血管分布的变化 联合治疗，并将其与传统能量多普勒和对比增强超声（CEUS、 使用非肾毒性微/纳米气泡造影剂）。我们假设肿瘤的变化 通过超声波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 名 mRCC 患者，在术前进行多普勒超声和 CEUS 评估 治疗后以及伊匹单抗和纳武单抗联合治疗 3 周和 6 周后。我们的试点研究目标 确定 1) 多普勒超声和/或 CEUS 是否可以最早在术后 3 和/或 6 周检测到变化 开始免疫治疗； 2) 如果超声波检测到的变化与标准测量的反应相关- 治疗 12 周后进行非护理 CT 扫描； 3）哪个超声时间点（3周或6周）更好 预计 12 周后会有结果。我们将使用超声波成像来加速检测反应 联合使用伊匹单抗+纳武单抗。如果成功的话，我们可以将我们的方法应用于其他肿瘤和药物， 因为肿瘤血管的变化是大多数癌症治疗反应的关键机制。