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Understanding IDH mutant gliomas

了解 IDH 突变神经胶质瘤

基本信息

批准号：
10926357
负责人：
Jing Wu
金额：
$ 66.33万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926357
关键词：
Address Cells Clinical Clinical Management Clinical Trials Compensation Correlative Study Detection Development Disease Disease Progression Early Diagnosis Epigenetic Process Evaluation Glioblastoma Glioma Goals Image Immune Immune checkpoint inhibitor Immunocompetence Immunohistochemistry Immunotherapy Indolent Isocitrate Dehydrogenase 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 Proliferating 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 empowerment imaging modality insight magnetic resonance spectroscopic imaging metabolic imaging mutant neoantigens neuro-oncology peripheral blood prevent prospective response secondary endpoint tool transcriptome sequencing treatment response tumor tumor microenvironment tumor progression

项目摘要

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-mutant 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 hyperpolarized 13Cpyruvate MRS imaging (HP 13C 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 gliomas. The second part of the study is to determine whether tumor mutation burden correlates with the response to CPI 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. Upon completion of the study, we will provide the first prospective evidence to address a long-standing question in the field of neuro-oncology: whether TMB correlates with immune CPI in IDH-mutant gliomas. Additionally, the results of the correlative studies will provide insights into response to immunotherapy in IDH-mutant gliomas.

IDH突变型神经胶质瘤在表型、遗传和表观遗传上是独特的。大多数IDH突变型胶质瘤是低级别胶质瘤（LGG），与野生型IDH相比，疾病进程更缓慢，总体预后更好。然而，几乎所有这些都转化为更高级别的胶质瘤（HGG）。目前，没有治疗方法来延迟或预防这种转化，主要是由于缺乏对这种更高级别的转化（HT）在疾病过程中如何，为什么以及何时发生的理解。当LGG在IDH突变型胶质瘤中转化为更高级别时，体细胞突变数量增加，导致肿瘤快速进展。这些转化的肿瘤的一个子集发展出非常高数量的突变，这种现象被称为超变表型（HMP），并且不再对当前可用的疗法有反应。这种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试验，允许纵向监测水平的2-HG，乳酸/丙酮酸在IDH突变的胶质瘤的比例，通过使用质子磁共振波谱（1H-MRS）和超极化13 C丙酮酸MRS成像（HP 13 C丙酮酸MRSI）的方法。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。这部分研究使HT和组织采集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。选择具有HMP的肿瘤将进一步使另一项临床试验能够评估IDH突变胶质瘤中的免疫检查点抑制剂（ICPI）治疗。研究的第二部分是确定肿瘤突变负荷是否与IDH突变胶质瘤对CPI的反应相关。为了解决这一具体目标，一项II期临床试验将比较ICPI治疗的疗效，使用抗PD-1抗体nivolumab，在有和没有HMP的IDH突变胶质瘤患者之间进行。主要目的是测量两个队列患者6个月时的无进展生存率。总生存期和12个月时的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织化学和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中的细胞因子特征。还将测量肿瘤和外周血单核细胞中的T细胞受体（TCR）库。研究完成后，我们将提供第一个前瞻性证据来解决神经肿瘤学领域的一个长期存在的问题：TMB是否与IDH突变胶质瘤中的免疫CPI相关。此外，相关研究的结果将为IDH突变型胶质瘤对免疫治疗的反应提供见解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tumor mutational burden and immunotherapy in gliomas.

DOI：
10.1016/j.trecan.2021.08.005
发表时间：
2021-12
期刊：
Trends in cancer
影响因子：
18.4
作者：
Merchant M;Ranjan A;Pang Y;Yu G;Kim O;Khan J;Wu J
通讯作者：
Wu J

Perspectives on IDH Mutation in Diffuse Gliomas.

关于弥漫性神经胶质瘤中IDH突变的观点。

DOI：
10.1016/j.trecan.2018.06.006
发表时间：
2018-09
期刊：
Trends in cancer
影响因子：
18.4
作者：
Su YT;Phan FP;Wu J
通讯作者：
Wu J

A Survey of the Neuro-Oncology Landscape.

神经肿瘤学景观调查。

DOI：
10.3988/jcn.2018.14.1.8
发表时间：
2018
期刊：
Journal of clinical neurology (Seoul, Korea)
影响因子：
0
作者：
Lukas,RimasV;Wu,Jing;Dey,Mahua;Buerki,RobinA;Byrne,RichardW;Dohrmann,GeorgeJ
通讯作者：
Dohrmann,GeorgeJ

Targeting nicotinamide adenosine dinucleotide (NAD) in diffuse gliomas.

靶向弥漫性神经胶质瘤中的烟酰胺腺苷二核苷酸 (NAD)。