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.
The proposed research is relevant to public health because by the end of the project we will have fully characterized and demonstrated the use of a non-invasive tool to quantify metabolic changes in primary malignant brain tumors bearing mutations of isocitrate dehydrogenase (IDH) due to an immunotherapy- based treatment. We will have a succinct understanding of where measurement variations occur and why. We will be ready to use these measures as part of future development of IDH mutated immunotherapy intervention, and will have pilot data to present to industrial partners for continuing its development as a robust tool for diagnosis and therapeutic decision making in the clinic.
