Quantitative Staging and Therapeutic Response in IDH-1 Mutated Glioblastomas

目标：我们将充分描述一组使用2- 羟基戊二酸（2HG）监测异柠檬酸脱氢酶1突变的免疫干预 (IDH1+）神经胶质瘤。杜克大学将于2016年春季开始招募，进行一项临床试验，以测试安全性和 IDH1+疫苗在II级神经胶质瘤患者中的免疫原性;这将是该提案的母试验。 背景：胶质母细胞瘤是儿童和年轻人中最恶性的原发性脑肿瘤， 中位总生存期<15个月。低级别胶质瘤患者通常进展为这种致命肿瘤 10年内的类型。目前对这些肿瘤的治疗是失能的，并受到非特异性毒性的限制。在 相比之下，免疫疗法有望成为一种非常精确的治疗方法。一种高度保守的 杜克大学的研究人员发现了IDH1活性位点的特异性突变。这种突变 发生在> 70%的几乎所有胶质瘤亚型中，并用于开发IDH1特异性疫苗。直接 IDH1突变的结果是癌代谢物2HG的极端过表达， 非侵入性地使用磁共振波谱。"野生" IDH1胶质瘤中的2HG浓度低于 MRS测量使2HG成为IDH1+突变神经胶质瘤的特异性标志物。方法：我们将创建一个 标准化MRS方案，解释疫苗接种期间肿瘤表现的初始变化 在肿瘤切除之前的应用阶段。我们与一个联盟合作，进行MRS的临床翻译 方法在马萨诸塞州总医院（MGH）由Ovidiu Andronesi博士领导。我们将创建一个 使用1）MGH 2HG经过验证的MEGA-LASER脉冲序列进行2HG测量的标准协议， Siemens MR扫描仪; 2）用于纵向体素重新定位的Siemens自动体素对齐软件; 3）Soher博士的开源"Vespa"软件，用于光谱模拟和MEGA-LASER数据拟合。 我们将在多个时间点的工作流程中证明该方法的可行性和可重复性，并测量 同一天代谢物的变异系数，以支持其在II期试验中的使用。我们将测量2HG 在所有接受IDH1+疫苗的患者中。患者将在我们的研究Siemens Trio扫描仪上进行扫描， 在大约6 - 8周的5个时间点，他们在手术切除之前接受疫苗。影响：我们的 长期假设是针对2HG优化的MRS方案可以为临床医生提供稳健的代谢 这些措施提供了直接的，可能是更早的措施，治疗干预的效果，而不是 其他MR测量，例如有/无造影剂的肿瘤增强。目前的建议提供了一个 无与伦比的机会，与我们的母公司I期免疫治疗试验合作， 优化用于定量肿瘤代谢的良好表征的工具，以用于随后的II期试验。 我们将确定在该患者集中采取2HG措施的最佳实践，并证明 就患者耐受性和数据稳健性而言，将此措施纳入我们的研究/临床工作流程中。

Objective: We will fully characterize a set of best practices for using quantitative measures of 2- hydroxyglutarate (2HG) to monitor an immunotherapeutic intervention in isocitrate dehydrogenase 1 mutated (IDH1+) gliomas. Recruitment begins at Duke in Spring 2016 for a clinical trial to test safety and immunogenicity of an IDH1+ vaccine in grade II gliomas patients; this will be the parent trial for this proposal. Background: Glioblastoma, the most malignant primary brain tumor in children and young adults, has a median overall survival of <15 months. Patients with lower grade gliomas typically progress to this lethal tumor type within 10 years. Current therapy for these tumors is incapacitating and limited by non-specific toxicity. In contrast, immunotherapy promises an exquisitely precise therapeutic approach. A highly conserved and tumor specific mutation exclusively at the IDH1 active site was discovered by researchers at Duke. This mutation occurs in >70% of almost all glioma subtypes and was used to develop an IDH1 specific vaccine. A direct result of the IDH1 mutation is the extreme overexpression of the onco-metabolite 2HG which can be measured non-invasively using MR spectroscopy. 2HG concentrations in ‘wild’ IDH1 gliomas are below the level of measurement of MRS making 2HG a specific marker for IDH1+ mutated gliomas. Approach: We will create a standardized MRS protocol that accounts for initial variations in tumor presentation during the vaccine application period, prior to tumor resection. We have partnered with a consortium for clinical translation of MRS methods at Massachusetts General Hospital (MGH) headed by Dr. Ovidiu Andronesi. We will create a standard protocol for 2HG measures using 1) the MGH 2HG proven MEGA-LASER pulse sequence for Siemens MR scanners; 2) Siemens’ automatic voxel alignment software for longitudinal voxel re-positioning; and, 3) Dr. Soher’s open source “Vespa” software for spectral simulation and fitting of the MEGA-LASER data. We will demonstrate feasibility and repeatability of the method in a multiple time point workflow, and measure same-day metabolite coefficients of variance in order to power its use in Phase II trials. We will measure 2HG in all patients receiving the IDH1+ vaccine. Patients will be scanned on our research Siemens Trio scanner at five time points across approximately 6-8 weeks they receive vaccine prior to surgical resection. Impact: Our long-term hypothesis is that an MRS protocol optimized for 2HG can provide clinicians with robust metabolic measures which provide direct, and possibly earlier, measures of the effects of therapeutic interventions than other MR measures such as tumor enhancement with/without contrast. The current proposal provides an unparalleled opportunity to work collaboratively with our parent Phase I immunotherapy treatment trial to optimize a well characterized tool for quantitation of tumor metabolism for use in subsequent Phase II trials. We will determine best practices for taking 2HG measures in this patient set and demonstrate the feasibility of including this measure into our research/clinical workflow in terms of patient tolerance and data robustness.