Integration of single cell sequencing as a biomarker of PARP inhibitor response for IDH1 and IDH2 mutated AML and MDS

整合单细胞测序作为 IDH1 和 IDH2 突变 AML 和 MDS 的 PARP 抑制剂反应的生物标志物

• 批准号: 10337798
• 负责人: PATRICIA M. LORUSSO
• 金额: $ 12.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337798
• 关键词: Affect; Biological Markers; Blood specimen; CTLA4 gene; Case Study; Cells; Clinical Trials; Cryopreservation; Development; Effectiveness; Enrollment; Flow Cytometry; Grant; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Individual; Intracranial Neoplasms; Myelogenous; Myeloid Cells; Nivolumab; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Pre-Clinical Model; Process; Radiation; Radiation therapy; Radiology Specialty; Radiosurgery; Recurrence; Recurrent disease; Relapse; Reproducibility; Resistance; Safety; Salvage Therapy; Sampling; Solid Neoplasm; T-Lymphocyte; Time; Validation; inhibitor/antagonist; ipilimumab; meningioma; peripheral blood; potential biomarker; predictive marker; programmed cell death protein 1; response; synergism; treatment response

Project Summary/Abstract Meningioma is the most common intracranial tumor and affects approximately 150,000 individuals in the USA. Approximately 10-20% of them will eventually develop recurrent disease despite standard surgery and radiation therapy (RT). There is currently no effective salvage therapy for radiation-relapsed meningioma. Preclinical models suggest possible synergy when immune checkpoint inhibitors of the programmed-death-1 (PD-1) and cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) pathways are administered with concurrent RT, and anti-PD-1 inhibitor has shown promising activity against meningioma in cases reports. The ETCTN 10186 study is a phase I/II study that evaluates the safety and efficacy of combining anti-PD-1 and anti-CTLA-4 inhibitors with multi-fraction stereotactic radiosurgery for radiation-relapsed high- grade meningioma. Although predictive biomarkers for immunotherapy response have not been well established, specific T-cells or myeloid cells in peripheral blood have shown correlations with the treatment response to anti-PD-1 or anti-CTLA-4 inhibitors in previous clinical trials for solid tumors. The objective of the proposed study is to leverage the blood samples collected in the ETCTN study to discover potential biomarkers to predict immunotherapy response. The specific aim is to determine if peripheral T-cell or myeloid dynamics as assessed using multiparameter flow cytometry would correlate with treatment response. Twelve patients have already been enrolled in the ongoing ETCTN study, and their peripheral blood mononuclear cells (PBMCs) at baseline and weeks 4 and week 12 during treatment have been centrally processed and cryopreserved. These PBMC samples will be analyzed by multiparameter flow cytometry to evaluate the phenotype changes of peripheral T-cells and myeloid cells during treatment. The changes over time and the correlation with radiological response will be examined to generate candidate peripheral blood biomarkers for further development and validation. Once specific candidate phenotypes are identified, the reproducibility of quantifying these cellular subsets using flow cytometry will also be evaluated.

项目概要/摘要 脑膜瘤是最常见的颅内肿瘤，影响约 150,000 人 在美国的个人。其中大约 10-20% 最终会出现复发性疾病 尽管有标准的手术和放射治疗（RT）。目前尚无有效救援 放射复发性脑膜瘤的治疗。临床前模型表明，当 程序性死亡 1 (PD-1) 和细胞毒性 T 淋巴细胞的免疫检查点抑制剂 相关蛋白 4 (CTLA-4) 途径与同时 RT 和抗 PD-1 一起施用 在病例报告中，抑制剂显示出对抗脑膜瘤的良好活性。 ETCTN 10186 研究是一项 I/II 期研究，评估抗 PD-1 和 抗 CTLA-4 抑制剂联合多分次立体定向放射外科治疗放射复发性高 级脑膜瘤。尽管免疫治疗反应的预测生物标志物尚未被证实 外周血中已明确的特定 T 细胞或骨髓细胞已显示出相关性 与先前临床试验中抗 PD-1 或​​抗 CTLA-4 抑制剂的治疗反应 实体瘤。拟议研究的目的是利用收集的血液样本 ETCTN 研究旨在发现预测免疫治疗反应的潜在生物标志物。这 具体目的是确定外周 T 细胞或骨髓动力学是否如使用评估的那样 多参数流式细胞术与治疗反应相关。十二名患者有 已入组正在进行的 ETCTN 研究，他们的外周血单核细胞 基线以及治疗期间第 4 周和第 12 周的细胞 (PBMC) 已集中 处理并冷冻保存。这些 PBMC 样本将通过多参数流进行分析 细胞计数法评估外周 T 细胞和骨髓细胞的表型变化 治疗。随着时间的变化以及与放射反应的相关性将是 检查以生成候选外周血生物标志物以供进一步开发和 验证。一旦确定了特定的候选表型，量化的再现性 还将使用流式细胞术评估这些细胞亚群。