Understanding IDH mutant gliomas

了解 IDH 突变神经胶质瘤

• 批准号: 10702708
• 负责人: Jing Wu
• 金额: $ 58.06万
• 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/10702708
• 关键词: Address; Cells; Clinical; Clinical Management; Clinical Trials; Correlative Study; Detection; Development; Disease; Disease Progression; Early Diagnosis; Epigenetic Process; Evaluation; Financial compensation; Glioblastoma; Glioma; Goals; Image; Immune; Immune checkpoint inhibitor; Immunocompetence; Immunohistochemistry; Immunotherapy; Indolent; Innovative Therapy; Isocitrate Dehydrogenase; Lead; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Molecular; Monitor; Mutate; Mutation; Nivolumab; Outcome; Oxidative Phosphorylation; Patients; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Phenotype; Pre-Clinical Model; Process; Prognosis; Progression-Free Survivals; Protocols documentation; Protons; Pyruvate; Sampling; Signal Transduction; Solid Neoplasm; Somatic Mutation; Survival Rate; T-cell receptor repertoire; Testing; Therapeutic; Time; Tissues; Tumor Burden; Tumor Tissue; Warburg Effect; aerobic glycolysis; anti-PD1 antibodies; checkpoint therapy; cohort; comparative efficacy; cytokine; effective therapy; imaging modality; magnetic resonance spectroscopic imaging; metabolic imaging; mutant; neoantigens; neuro-oncology; peripheral blood; prevent; response; secondary endpoint; tool; transcriptome sequencing; treatment response; tumor; tumor microenvironment; tumor progression

IDH-mutant gliomas are unique phenotypically, genetically and epigenetically. Most IDH-mutant gliomas are lower-grade gliomas (LGG) with a more indolent disease process and an overall better prognosis than those with wild-type IDH. However, 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 responds 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 trial to allow the longitudinal monitoring of the level of 2-HG, the ratio of lactate/pyruvate in IDH-mutated gliomas by using proton magnetic resonance spectroscopy (1H-MRS) and 13C hyperpolarized pyruvate MRS imaging (13C HP Pyruvate MRSI) 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 the progression-free survival rate at 6 months in two cohorts of the patient. Overall survival and PFS at 12 months 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 include the 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突变胶质瘤具有独特的表型、遗传和表观遗传特征。大多数IDH突变胶质瘤是低级别胶质瘤（LGG），与野生型IDH相比，疾病过程更缓慢，总体预后更好。然而，几乎所有的胶质瘤都会转化为更高级别的胶质瘤（HGG）。目前，还没有治疗方法来延缓或预防这种转化，主要是因为缺乏对这种高级别转化（HT）在疾病过程中如何、为什么以及何时发生的理解。在idh突变的胶质瘤中，当LGGs转变为更高级别时，会积累更多的体细胞突变，导致肿瘤快速进展。这些转化肿瘤的一个子集发生了非常多的突变，这种现象被称为超突变表型（HMP），并且不再对当前可用的治疗有反应。由于缺乏足够的临床前模型，这种公认的临床现象并没有得到很好的理解。我们开展了一项临床试验，通过质子磁共振波谱（1H-MRS）和13C超极化丙酮酸磁共振成像（13C HP pyruvate MRSI）方法，对idh突变胶质瘤中2-HG水平、乳酸/丙酮酸比值进行纵向监测。该方案将包括在临床疾病进展和/或成像信号改变时对肿瘤组织进行采样。这部分研究使HT和组织获取的潜在非侵入性早期检测成为可能，使我们能够询问HT/HMP的分子和代谢机制。HMP肿瘤的选择将进一步支持另一项临床试验，以评估免疫检查点抑制剂（ICPI）治疗IDH突变胶质瘤HMP患者。研究的第二部分是确定在IDH突变型胶质瘤疾病进展后，HMP肿瘤是否比无HMP的肿瘤对这种免疫治疗有更好的反应。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nivolumab的ICPI治疗在有和没有HMP的idh突变胶质瘤患者之间的疗效。主要目的是测量两组患者6个月时的无进展生存率。总生存期、12个月PFS和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织化学和RNA测序评估肿瘤微环境的免疫谱；外周血中免疫细胞的免疫能力和细胞因子谱。T细胞受体（TCR）库在肿瘤和外周血单核细胞也将被测量。如果研究假设得到证实，将为idh突变型胶质瘤患者建立一种创新有效的治疗方法。