Understanding IDH mutant gliomas

了解 IDH 突变神经胶质瘤

• 批准号: 10262498
• 负责人: Jing Wu
• 金额: $ 56.5万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262498
• 关键词: Address; Cells; Clinical; Clinical Research; Clinical Trials; Correlative Study; Disease; Disease Progression; Early Diagnosis; Epigenetic Process; Evaluation; Glioma; Goals; Image; Immune; Immune checkpoint inhibitor; Immunocompetence; Immunohistochemistry; Immunotherapy; Indolent; Innovative Therapy; Magnetic Resonance Spectroscopy; Measures; Metabolic; Molecular; Monitor; Mutate; Mutation; Nivolumab; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Phenotype; Pre-Clinical Model; Process; Progression-Free Survivals; Protocols documentation; Protons; Pyruvate; Sampling; Signal Transduction; Somatic Mutation; Survival Rate; T-cell receptor repertoire; Testing; Therapeutic; Time; Tissues; Tumor Burden; Tumor Tissue; aerobic glycolysis; anti-PD1 antibodies; checkpoint therapy; cohort; comparative efficacy; cytokine; effective therapy; magnetic resonance spectroscopic imaging; mutant; neoantigens; neuro-oncology; novel; outcome forecast; peripheral blood; prevent; secondary endpoint; tool; transcriptome sequencing; treatment response; tumor; tumor microenvironment; tumor progression

IDH-mutated gliomas are unique phenotypically, genetically and epigenetically. Although patients with IDH-mutated gliomas have lower grade gliomas (LGG) with a more indolent disease process and a better prognosis than those with wild-type IDH, almost all of them transform to a higher-grade glioma (HGG). Currently, there are no treatments to delay or prevent this transformation, largely due to the lack of understanding of how, why and when this higher-grade transformation (HT) occurs during the course of the disease. An increased number of somatic mutations are accumulated when LGGs transform to a higher grade in IDH-mutated gliomas, leading to a rapid tumor progression. A subset of these transformed tumors develops a very high number of mutations, a phenomenon referred to as the hypermutator phenotype (HMP) and no longer respond to the currently available therapies. This well-established clinical phenomenon is not well-understood partly due to the lack of adequate preclinical models. We developed a clinical study to allow the longitudinal monitoring of the level of 2-HG and aerobic glycolysis (ratio of lactate/pyruvate or lactate turnover rate) in IDH-mutated LGGs by using proton magnetic resonance spectroscopy (1H-MRS) and 13C hyperpolarized pyruvate MRS imaging (13C HP Pyruvate MRSI)/13C MRS approaches. The protocol will include sampling the tumor tissue at the time of clinical disease progression and/or imaging signal change. This part of the study enables potential non-invasive early detection of HT and tissue acquisition that allows us to interrogate the molecular and metabolic mechanisms of HT/HMP. The selection of tumors with HMP will further empower another clinical trial to evaluate an immune checkpoint inhibitor (ICPI) treatment in IDH mutant glioma patients with HMP. The second part of the study is to determine whether tumors with HMP respond better to this immune therapy than those without HMP after disease progression in IDH mutant gliomas. To address this specific aim, a Phase II clinical trial will compare the efficacy of ICPI therapy, using an anti-PD-1 antibody, nivolumab, between IDH-mutant gliomas patients with and without HMP. The primary objective is to measure progression-free survival rate at 6 months in two cohorts of the patient. Overall survival and PFS at 12 month and overall survival are the secondary endpoints. Neoantigen and tumor-specific mutation loads from the tumor tissues will be correlated with treatment response. Other correlative studies including evaluation of immune profiles of the tumor microenvironment by immunohistochemistry and RNA sequencing; immune competency of immune cells and cytokine profile in peripheral blood. T cell receptor (TCR) repertoire in tumor and peripheral blood mononuclear cells will be measured as well. If the study hypothesis is confirmed, an innovative and effective therapy will be established for patients with IDH-mutant glioma that has developed a hypermutator phenotype.

IDH 突变的神经胶质瘤在表型、遗传和表观遗传上都是独特的。尽管IDH突变型胶质瘤患者的低级别胶质瘤（LGG）比野生型IDH患者的疾病过程更加惰性且预后更好，但几乎所有患者都会转化为高级别胶质瘤（HGG）。目前，尚无治疗方法可以延迟或阻止这种转变，这主要是由于缺乏对疾病过程中这种高级转变（HT）如何、为何以及何时发生的了解。当 IDH 突变神经胶质瘤中 LGG 转化为更高级别时，体细胞突变数量会增加，从而导致肿瘤快速进展。这些转化肿瘤的一部分会产生大量突变，这种现象被称为超突变表型（HMP），并且不再对当前可用的疗法做出反应。这种公认的临床现象尚未得到充分理解，部分原因是缺乏足够的临床前模型。我们开展了一项临床研究，通过使用质子磁共振波谱 (1H-MRS) 和 13C 超极化丙酮酸 MRS 成像 (13C HP 丙酮酸 MRSI)/13C MRS 方法，对 IDH 突变 LGG 中的 2-HG 和有氧糖酵解水平（乳酸/丙酮酸比率或乳酸周转率）进行纵向监测。该方案将包括在临床疾病进展和/或成像信号变化时对肿瘤组织进行采样。这部分研究能够实现 HT 和组织采集的潜在非侵入性早期检测，使我们能够探究 HT/HMP 的分子和代谢机制。选择使用 HMP 的肿瘤将进一步授权另一项临床试验来评估免疫检查点抑制剂 (ICPI) 对使用 HMP 的 IDH 突变神经胶质瘤患者的治疗。该研究的第二部分是确定 IDH 突变神经胶质瘤疾病进展后，含有 HMP 的肿瘤是否比不含 HMP 的肿瘤对这种免疫疗法有更好的反应。为了实现这一特定目标，一项 II 期临床试验将比较使用抗 PD-1 抗体纳武单抗 (nivolumab) 的 ICPI 治疗在有和没有 HMP 的 IDH 突变神经胶质瘤患者之间的疗效。主要目标是测量两组患者 6 个月时的无进展生存率。 12 个月时的总生存期和 PFS 以及总生存期是次要终点。来自肿瘤组织的新抗原和肿瘤特异性突变负荷将与治疗反应相关。其他相关研究包括通过免疫组化和RNA测序评估肿瘤微环境的免疫特征；免疫细胞的免疫能力和外周血细胞因子谱。肿瘤和外周血单核细胞中的 T 细胞受体 (TCR) 也将被测量。如果研究假设得到证实，将为患有高突变表型的 IDH 突变神经胶质瘤患者建立一种创新且有效的疗法。