Biomarkers of Response to Immuno-chemotherapy & oliGometastatic Hypofractionated radioTherapy (BRIGHT) for Lung Cancer: Synergy of PET/CT Imaging and Peripheral Blood Assays

免疫化疗反应的生物标志物

• 批准号: 10542766
• 负责人: Stephen R. Bowen
• 金额: $ 59.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542766
• 关键词: Biological Assay; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Control; Cells; Cessation of life; Clinical; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Complex; Consensus; Data; Development; Disease; Early Intervention; Enrollment; External Beam Radiation Therapy; Financial Hardship; Future; Glycolysis; Image; Immune; Immune checkpoint inhibitor; Immune response; Immuno-Chemotherapy; Immunologic Markers; Immunophenotyping; Immunotherapy; Intervention; Lesion; Ligands; Link; Malignant neoplasm of lung; Metabolic; Monitor; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Observational Study; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Phenotype; Positron-Emission Tomography; Precision Medicine Initiative; Precision therapeutics; Progression-Free Survivals; Progressive Disease; Proteins; Radiation; Radiation therapy; Radio; Risk; Site; Standardization; Systemic Therapy; Systemic disease; T-Cell Receptor; Therapeutic; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Tumor Volume; United States National Institutes of Health; Validation; X-Ray Computed Tomography; anti-PD-1; biomarker identification; biomarker signature; burden of illness; cancer survival; chemotherapy; circulating biomarkers; clinical imaging; cytokine; disorder control; fluorodeoxyglucose positron emission tomography; high risk; imaging biomarker; improved; improved outcome; individual patient; individual response; irradiation; learning strategy; monocyte; multidisciplinary; outcome prediction; patient stratification; peripheral blood; phase II trial; predictive marker; prognostic value; prognostication; programmed cell death ligand 1; prospective; quantitative imaging; radiation response; radiomics; randomized trial; response; response biomarker; risk stratification; standard of care; support tools; survival outcome; synergism; treatment response; tumor; uptake

ABSTRACT Management of patients with metastatic non-small cell lung cancer (NSCLC) requires navigation of an increasingly diverse therapeutic landscape. Although immune checkpoint inhibitors (ICI) of anti-programmed cell death 1 (PD1) and its ligand PDL1, in combination with chemotherapy (chemoICI), are standard of care for metastatic NSCLC and have improved survival in some patients, the majority are subject to treatment-related toxicity at significant financial burden with little clinical benefit. Radiation therapy can prolong survival in patients with limited sites of metastatic disease (oligometastatic), or limited sites of progressive disease (oligoprogression) on systemic therapy, but no consensus exists on which patients and lesions would benefit from irradiation. Patient selection and treatment adaptation through early response assessment is an unmet need to increase the effective combination of chemotherapy, immunotherapy, and radiation therapy in metastatic NSCLC and improve outcomes. Biomarkers are critical to our understanding of complex response patterns to chemoICI and radiation. In patients with newly diagnosed metastatic NSCLC starting chemoICI per standard of care, we propose to assess and monitor treatment response by combining positron emission tomography (PET) imaging of macroscopic disease burden and circulating immunologic biomarkers of occult systemic disease burden in support of precision therapy through the following aims: (1) construct clinical PET imaging and circulating immunologic biomarker signatures of chemoICI response patterns to risk stratify patients into (a) early widespread progression, (b) oligoprogression, and (c) responsive disease; (2) construct clinical PET imaging and circulating immunologic biomarker signatures of oligoprogressive radiation therapy response patterns to identify patients and lesions that benefit from ablative radiation; and (3) correlate localized clinical PET imaging and global circulating immunologic biomarkers with survival outcomes. Fluorodeoxyglucose (FDG) PET scans and peripheral blood draws will be performed prior to chemoICI, 3 weeks into chemoICI, and 12 weeks into chemoICI. For patients who develop oligoprogressive disease, we will acquire FDG PET scans and peripheral blood prior to and 1-month post radiation therapy. We will develop combined quantitative PET imaging and circulating immunologic biomarker signatures of chemoICI and radiation response that stratify patients into the following groups: (i) high-risk patients predicted to develop rapid widespread progressive disease who require aggressive second-line systemic therapy, (ii) moderate-risk patients predicted to develop oligoprogressive disease who require consolidation radiation to high-risk lesion targets, (iii) low-risk patients predicted to have durable long-term response to first-line therapy. Successful completion of this project will support the launch of a clinical trial on biomarker response-adaptive chemoICI and radiation therapy in patients with metastatic non-small cell lung cancer, in order to improve cancer control and survival.

抽象的 转移性非小细胞肺癌 (NSCLC) 患者的治疗需要导航 日益多样化的治疗景观。虽然免疫检查点抑制剂（ICI）是抗程序性的 细胞死亡 1 (PD1) 及其配体 PDL1 与化疗 (chemoICI) 相结合，是以下患者的标准治疗方法： 转移性非小细胞肺癌（NSCLC），部分患者的生存率有所提高，但大多数患者都接受了与治疗相关的治疗 毒性造成巨大的经济负担，但临床效益却很小。放射治疗可以延长患者的生存期 患有有限部位转移性疾病（寡转移）或有限部位进展性疾病的患者 （寡进展）全身治疗，但对于哪些患者和病变将受益尚无共识 免受辐射。通过早期反应评估来选择患者和治疗适应尚未得到满足 需要增加化疗、免疫治疗和放射治疗的有效联合治疗 转移性非小细胞肺癌并改善预后。生物标志物对于我们理解复杂反应至关重要 chemoICI 和放射的模式。在新诊断的转移性 NSCLC 患者中开始化疗 ICI 护理标准，我们建议通过结合正电子发射来评估和监测治疗反应 宏观疾病负担和隐匿性循环免疫生物标志物的断层扫描 (PET) 成像 通过以下目标支持精准治疗的全身疾病负担：（1）构建临床PET chemoICI 反应模式的成像和循环免疫生物标志物特征以进行风险分层 患者进入(a)早期广泛进展、(b)寡进展和(c)反应性疾病； (2)构建 寡渐进放射治疗的临床 PET 成像和循环免疫生物标志物特征 识别受益于消融放射的患者和病变的反应模式； (3) 关联本地化 临床 PET 成像和全球循环免疫生物标志物与生存结果。 氟脱氧葡萄糖 (FDG) PET 扫描和外周血抽取将在 chemoICI 之前进行，3 进行 chemoICI 周，以及进行 chemoICI 12 周。对于出现寡进行性疾病的患者，我们将 在放射治疗前和放射治疗后 1 个月采集 FDG PET 扫描和外周血。我们将开发 结合定量 PET 成像和 chemoICI 和循环免疫生物标志物特征 将患者分为以下几组的放射反应： (i) 预计发生的高危患者 需要积极二线全身治疗的快速广泛进展性疾病，(ii) 中等风险 预计会出现寡进行性疾病且需要对高风险病变进行巩固放射的患者 目标，(iii) 预计对一线治疗有持久长期反应的低风险患者。成功的 该项目的完成将支持生物标志物反应适应性 chemoICI 临床试验的启动 对转移性非小细胞肺癌患者进行放射治疗，以改善癌症控制 和生存。