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.
