Clinical evaluation and non-invasive monitoring of Vorasidenib in combination with tumor specific peptide PEP-IDH1M vaccine therapy in patients with recurrent mutant IDH1 glioma

摘要-异柠檬酸脱氢酶1（mIDH 1）基因突变的鉴定导致了显着的 低级别胶质瘤的研究进展较低级别的胶质瘤，WHO II-III级，可以有较长的 中位总生存期高于WHO IV级，但他们仍然会发生显著的神经系统疾病， 死亡率，因为标准治疗不能治愈。需要新的治疗方法来针对较低级别 胶质瘤，以改善这些患者的生活质量和生存。mIDH 1突变存在于 70%的胶质瘤亚型，并且是低级别胶质瘤的致癌驱动因素，导致极端 癌代谢物R-2-羟基戊二酸（2 HG）的过量产生。因为突变是肿瘤特有的， 它为开发下列药物提供了重要的靶点：1）靶向治疗剂，如mIDH 1/2抑制剂， 免疫疫苗（例如，vorasidenib和PEPIDH 1 M）和2）非侵入性肿瘤诊断 和监测方法。最近，据报道， 除了驱动低级别神经胶质瘤的肿瘤发生外，2 HG还具有免疫抑制作用。的作用 作为胶质瘤形成的驱动因素，现在又诱导抗肿瘤T细胞的免疫抑制，2 HG被认为是一种免疫抑制剂。 治疗低级别胶质瘤的关键目标因此，我们建议进行一项联合治疗的临床试验， vorasidenib和PEPIDH 1 M。我们假设vorasidenib早期抑制2 HG， 随后或同时给予PEPIDH 1 M疫苗以产生更强T细胞应答， 导致增加免疫介导的肿瘤细胞杀伤（特异性目的1）。在这个I期单中心临床试验中，我们 将决定这种组合方法的安全性。将按照CTCAE对毒性事件进行评价和分级 5.0的搜索. RANO标准将用于评估基于常规检查的放射学无进展生存期。 核磁共振成像。作为一个探索性的目标，我们将使用现有的高速成像技术纵向绘制2 HG在大脑中的分布。 磁共振光谱成像（MRSI）和离线处理，以监测vorasidenib的作用 （具体目标2）。最后，在临床试验的同时，我们将把经过验证的2 HG标测工具转换为 用于报告GE和Siemens扫描仪上的2 HG水平的标准化在制品（Works-in-progress，简称WP-S）包 DICOM工作流程（特定目标3）。这个项目建立在1）我们以前参与早期 PEPIDHM 1和vorasidenib的临床试验，其中我们还表征了纵向2 HG水平，以及2）我们的 在自动化MRS方法并将其转化为制造商支持的ERP方面拥有数十年的经验 包装件.

Abstract – The identification of mutations in the isocitrate dehydrogenase 1 (mIDH1) gene has led to significant advances in understanding lower grade gliomas. Lower grade gliomas, WHO grade II-III, can have a longer median overall survival than WHO grade IV, yet they still develop significant neurological morbidity and ultimately mortality, as standard of care therapies are not curative. New therapeutics are needed to target lower grade gliomas to improve quality of life outcomes and survival for these patients. The mIDH1 mutation exists in over 70% of glioma subtypes and is the oncogenic driver in lower grade gliomas by leading to the extreme overproduction of the oncometabolite R-2-hydroxyglutarate (2HG). Because the mutation is specific to the tumor, it provides significant targets for the development of: 1) targeted therapeutics, such as mIDH1/2 inhibitors and immunotherapeutic vaccines (e.g., vorasidenib and PEPIDH1M, respectively) and 2) non-invasive tumor diagnosis and monitoring methods, via magnetic resonance spectroscopy (MRS). More recently, it has been reported that in addition to driving the oncogenesis of lower grade gliomas, 2HG has immunosuppressive actions. Its role as a driver of gliomagenesis and now induction of immunosuppression of tumor-fighting T-cells places 2HG as a critical target in fighting lower grade gliomas. Thus, we propose a clinical trial for a combined therapy of vorasidenib and PEPIDH1M. We hypothesize that early suppression of 2HG by vorasidenib would allow subsequent or concurrent administration of PEPIDH1M vaccine to generate a more robust T-cell response and lead to increased immune-mediated tumor cell kill (Specific Aim 1). In this phase I, single-site clinical trial, we will determine the safety of this combinatorial approach. Toxicity events will be evaluated and graded by CTCAE 5.0 criteria. The RANO criteria will be used to assess radiographic progression-free survival based on routine MRI imaging. As an exploratory goal, we will map 2HG across the brain longitudinally using existing high-speed magnetic resonance spectroscopic imaging (MRSI) and offline processing to monitor the effects of vorasidenib (Specific Aim 2). Finally, in parallel with the clinical trial, we will convert the validated 2HG mapping tool into a standardized works-in-progress (WIP) package for reporting 2HG levels on both GE and Siemens scanner DICOM workflow (Specific Aim 3). This project builds on 1) our previous experiences participating in the early clinical trials for PEPIDHM1 and vorasidenib, where we also characterized longitudinal 2HG levels, and 2) our decades-long experience with automating MRS methods and translating them into manufacturer supported WIP packages.