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.

项目摘要 我们提出了一项试点研究，以检测对免疫疗法的反应。 治疗，使用多普勒超声和对比增强超声（CEU）来测量 转移性肾细胞癌（MRCC）患者的肿瘤血管性。生物标志物快速检测 迫切需要对RCC治疗的反应，因为并非所有患者都对一线治疗做出反应 联合CTLA-4免疫检查点抑制剂（ipilimumab）加上抗PD-1免疫检查点抑制剂 （Nivolumab）。然而，所有患者都忍受了这种组合治疗的副作用（疲劳，自身免疫 肝炎/甲状腺炎/肺炎等）同时等待护理标准计算机断层扫描（CT）成像。 目前，需要12周来通过测量CT肿瘤直径减少来评估反应，因为 在治疗12周之前，肿瘤大小不会显着变化。快速检测对RCC治疗的反应 将最大程度地减少使用无效的药物的使用，并允许患者停止无效的疗法，并仅继续 有效的疗法。我们发现基于成像的肿瘤血管的测量值，例如灌注CT 扫描可以检测到MRCC中对治疗的早期反应。但是这些需要潜在的肾毒性碘对比 代理和访问放射科。我们已经开发了高度敏感的，无对比的，血管 使用高级功率多普勒超声检查，可以在肿瘤学诊所的床边进行成像 直径小至1毫米的图像容器。现在，我们建议使用高级功率多普勒超声 一项试点研究，以评估肿瘤血管变化，在常规肿瘤学诊所就诊期间 将治疗结合在一起，并将其与传统的功率多普勒和对比度增强的超声进行比较（CEUS， 使用非氯毒性微/纳米气泡对比剂）。我们假设肿瘤的变化 通过超声测量的血管性可以比肿瘤的变化更早地检测到对治疗的反应 直径。我们将注册30名MRCC患者，以后用多普勒超声和CEU进行评估 治疗以及3周和6周的ipilimumab和Nivolumab疗法后。我们的试点研究目标 确定1）多普勒超声和/或CEU是否可以在3和/或6周后检测到变化 开始免疫疗法； 2）如果超声检测到的变化与标准测量的响应相关 治疗12周后，可以进行护理CT扫描； 3）哪个超声时间点（3周或6周）更好 预计结果为12周。我们将使用超声成像来加速检测对 联合ipilimumab + nivolumab。如果成功，我们可以将方法应用于其他肿瘤和药物， 由于肿瘤的变化是对大多数癌症疗法的反应的关键机制。