Using MRI and circulating tumor DNA to improve the interpretation of response to immunotherapy and targeted therapy in CNS metastases

利用 MRI 和循环肿瘤 DNA 改善对中枢神经系统转移免疫治疗和靶向治疗反应的解释

• 批准号: 10542435
• 负责人: Priscilla Kaliopi Brastianos
• 金额: $ 66.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542435
• 关键词: Address; Anatomy; Biological; Biological Markers; Blood; Blood Vessels; Brain; Breast; Cellularity; Clinical; Clinical Trials; Clonal Evolution; Collection; Data; Data Set; Disease; Genes; Genetic Heterogeneity; Goals; Histology; Image; Immune system; Immunotherapy; Inflammation; Leptomeninges; Location; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Metastatic Neoplasm to the Central Nervous System; Metastatic malignant neoplasm to brain; Monitor; Mutation; PD-1 inhibitors; Pathway interactions; Patients; Pattern; Perfusion; Pharmaceutical Preparations; Physiological; Play; Resistance; Role; Shapes; Tissue Sample; Tissues; Tumor Burden; Vertebral column; Work; brain magnetic resonance imaging; burden of illness; chemotherapy; contrast enhanced; genetic evolution; immune activation; immunotherapy trials; improved; improved outcome; insight; interest; novel therapeutics; patient population; patient subsets; pembrolizumab; radiological imaging; responders and non-responders; response; response biomarker; survival prediction; targeted treatment; tool; treatment response; trial enrollment; tumor; tumor DNA; tumor growth; tumor microenvironment; tumor progression

Project Summary/Abstract There is increasing interest in using immunotherapy or targeted therapy to treat brain metastases, including leptomeningeal disease from cancer. However, it can be challenging to interpret response to treatment or to understand patterns of response or resistance to treatment since serial tissue samples are difficult to obtain from the brain. Thus, there is a critical need to identify noninvasive makers of response or resistance to new therapies being evaluated in this understudied patient population. In this proposal, Aim 1 will combine circulating tumor DNA with sophisticated MRI scans to improve our ability to interpret response of brain metastases patients treated with pembrolizumab, a PD-1 inhibitor. With pembrolizumab, increase in contrast enhancement on MRI can be tumor progression or inflammation from successful re-activation of the immune system with treatment. We hypothesize that by combining a quantitative measure of tumor burden, specifically circulating tumor DNA, with MRI scans, we will be able to disambiguate true progression from pseudoprogression and, moreover, to understand mechanisms of response/resistance. Aim 2 will use circulating tumor DNA to shed light on the clonal evolution of brain metastases in response to targeted therapy, allowing for noninvasive means to understand response and resistance patterns. Aim 3 will address the clinical challenge of accurately determining radiographic response in patients with leptomeningeal disease from cancer. Similar to our hypothesis for parenchymal brain metastases, we expect that adding ctDNA to MRI will improve our ability to more reliably measure LMD response to treatment.

项目概要/摘要 人们对使用免疫疗法或靶向疗法治疗脑转移瘤越来越感兴趣， 包括癌症引起的软脑膜疾病。然而，解释对以下问题的反应可能具有挑战性 治疗或了解治疗的反应或抵抗模式，因为连续的组织样本是 很难从大脑中获取。因此，迫切需要确定反应或反应的非侵入性制造者。 在这个未被充分研究的患者群体中正在评估对新疗法的耐药性。 在该提案中，目标 1 将循环肿瘤 DNA 与复杂的 MRI 扫描相结合，以改善我们的研究 能够解释接受 PD-1 抑制剂派姆单抗治疗的脑转移患者的反应。和 派姆单抗（pembrolizumab），MRI 对比增强的增加可能是肿瘤进展或炎症 通过治疗成功重新激活免疫系统。我们假设通过结合定量 通过 MRI 扫描测量肿瘤负荷，特别是循环肿瘤 DNA，我们将能够消除歧义 从假进展到真正的进展，此外，了解反应/抵抗机制。 目标 2 将利用循环肿瘤 DNA 揭示脑转移瘤响应的克隆进化 靶向治疗，允许采用非侵入性手段来了解反应和抵抗模式。目标3将 解决准确确定软脑膜患者放射照相反应的临床挑战 癌症引起的疾病。与我们对实质脑转移的假设类似，我们期望添加 ctDNA 到 MRI 将提高我们更可靠地测量 LMD 对治疗反应的能力。