Understanding IDH mutant gliomas

了解 IDH 突变神经胶质瘤

• 批准号: 10487013
• 负责人: Jing Wu
• 金额: $ 69.94万
• 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/10487013
• 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; Prognosis; 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; 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突变的胶质瘤在遗传和表观遗传学上都是独特的表型。与野生型IDH相比，IDH突变型胶质瘤的恶性程度较低，病程较慢，预后较好，但几乎全部转化为较高级别的胶质瘤(HGG)。目前，还没有治疗方法来延缓或阻止这种转化，这主要是由于缺乏对疾病过程中如何、为什么以及何时发生这种更高级别的转化(HT)的了解。在IDH突变的胶质瘤中，当LGGs转化为更高级别时，体细胞突变的数量会增加，从而导致肿瘤的快速进展。这些转化的肿瘤中的一部分会产生非常高数量的突变，这种现象被称为超变异体表型(HMP)，不再对目前可用的治疗方法产生反应。这一公认的临床现象尚未得到很好的理解，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，纵向监测IDH突变的IGG的2-HG水平和有氧糖酵解(乳酸/丙酮酸或乳酸周转率)。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。该研究的这一部分使我们有可能无创地早期检测甲状旁腺激素和组织获取，从而使我们能够询问甲状旁腺激素/HMP的分子和代谢机制。选择带有HMP的肿瘤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)对患有HMP的IDH突变胶质瘤患者的治疗。研究的第二部分是确定在IDH突变的胶质瘤中，在疾病进展后，有HMP的肿瘤是否比没有HMP的肿瘤对这种免疫治疗有更好的反应。为了解决这一特定目标，第二阶段临床试验将比较使用抗PD-1抗体nivolumab的ICPI治疗在患有和不患有HMP的IDH突变胶质瘤患者之间的疗效。主要目标是测量两组患者6个月的无进展存活率。总生存期、12个月的PFS和总生存期是次要终点。肿瘤组织中的新抗原和肿瘤特异性突变载量将与治疗反应相关。其他相关研究包括通过免疫组织化学和RNA测序评价肿瘤微环境的免疫谱；免疫细胞的免疫能力和外周血中细胞因子的谱。还将测定肿瘤和外周血单核细胞中的T细胞受体(TCR)谱。如果研究假设得到证实，将为IDH突变的胶质瘤患者建立一种创新和有效的治疗方法，这些患者已经形成了高度突变的表型。