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

项目概要/摘要 脑膜瘤是最常见的颅内肿瘤，约有15万人患病 个人在美国。大约10-20%的人最终会发展为复发性疾病 尽管进行了标准手术和放射治疗（RT）。目前没有有效打捞 放射性复发脑膜瘤的治疗。临床前模型表明， 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 在病例报告中，抑制剂显示出对脑膜瘤有希望活性。ETCTN 10186 研究是一项I/II期研究，评估了抗PD-1和 抗CTLA-4抑制剂联合多分割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性生物标志物尚未被发现， 在外周血中已证实的特异性T细胞或髓样细胞显示出相关性， 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， 实体瘤这项拟议研究的目的是利用在 ETCTN研究发现潜在的生物标志物来预测免疫治疗反应。的 具体目的是确定是否使用评估的外周T细胞或骨髓动力学 多参数流式细胞术将与治疗反应相关。12名患者 已经参加了正在进行的ETCTN研究，他们的外周血单核细胞 在基线和治疗期间的第4周和第12周， 处理和冷冻保存。这些PBMC样本将通过多参数流式细胞仪进行分析。 流式细胞术来评估外周T细胞和髓系细胞的表型变化 治疗随时间的变化以及与放射反应的相关性将被 检查以产生用于进一步开发的候选外周血生物标志物， 验证。一旦确定了特定的候选表型，定量的可重复性 还将使用流式细胞术评价这些细胞亚群。

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.