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.

项目摘要/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%的人最终会发展为复发性疾病 尽管有标准的手术和放射治疗(RT)。目前还没有有效的救助措施 放射复发性脑膜瘤的治疗。临床前模型显示在以下情况下可能存在协同作用 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物- 相关蛋白4(CTLA-4)途径与同时RT和抗PD-1一起被给予 在病例报道中，抑制剂显示出良好的抗脑膜瘤活性。ETCTN 10186 这项研究是一项I/II期研究，评估联合抗PD-1和 多组分立体定向放射外科治疗放射复发率高的抗CTLA-4抑制剂 级别脑膜瘤。尽管免疫治疗反应的预测性生物标记物尚未被 外周血中成熟的、特定的T细胞或髓系细胞显示出相关性 在先前的临床试验中，对抗PD-1或抗CTLA-4抑制剂的治疗反应 实体瘤。这项拟议的研究的目的是利用在 ETCTN的研究旨在发现预测免疫治疗反应的潜在生物标志物。这个 具体目的是确定外周T细胞或髓系动力学是否如使用 多参数流式细胞术可能与治疗反应相关。12名患者有 已经参加了正在进行的ETCTN研究，他们的外周血单核细胞 治疗前和治疗期间第4周和第12周的细胞(PBMC)一直集中在 经过加工和超低温保存。这些PBMC样品将用多参数流动分析 流式细胞术检测外周血T细胞和髓系细胞的表型变化 治疗。随时间的变化及其与放射反应的相关性将是 检查以产生候选外周血液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，量化的重复性 使用流式细胞术的这些细胞亚群也将被评估。