Understanding IDH mutant gliomas

IDH突变的神经胶质瘤在表型、遗传学和表观遗传学上是独特的。虽然IDH突变的胶质瘤患者具有较低级别的胶质瘤（LGG），具有更惰性的疾病过程和比野生型IDH患者更好的预后，但几乎所有患者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突变的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子表型（HMP），并且不再对目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研究，通过使用质子磁共振波谱（1H-MRS）和13 C超极化丙酮酸MRS成像（13 C HP Pyruvate MRSI）/13 C MRS方法，纵向监测IDH突变LGG中2-HG和有氧糖酵解（乳酸/丙酮酸比或乳酸周转率）的水平。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的肿瘤将进一步授权另一项临床试验，以评估具有HMP的IDH突变型胶质瘤患者的免疫检查点抑制剂（ICPI）治疗。该研究的第二部分是确定在IDH突变胶质瘤疾病进展后，HMP肿瘤是否比没有HMP的肿瘤对这种免疫治疗的反应更好。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。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。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和有效的治疗方法。

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.