Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

Abstract

Introduction: Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system (CNS), accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15–20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients. Methods: Pre-treatment and on-treatment α-[11C]-methyl-L-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and temozolomide. Results: Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment. Conclusions: Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…Further clinical studies with [ 11 C]AMT-PET demonstrated the ability to differentiate radiation necrosis from recurrent gliomas (Alkonyi et al 2012), and showed a strong association of high tumor [ 11 C] AMT uptake parameters (SUVmax, SUVmean and tumor-to-background ratio) to a significantly decreased 1year survival (Kamson et al 2014). Although a recent clinical [ 11 C]AMT-PET study in 3 patients failed to demonstrate objective clinical responses to IDO inhibitor therapy, it did show heterogeneous intratumoral tracer uptake potentially reflecting IDO activity (Lukas et al 2019). Furthermore, these results indicate that [ 11 C]AMT-PET might be used for stratification of true progression versus pseudoprogression.…”

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

“…Given the importance of the kynurenine pathway in numerous cancers, it is increasingly recognised as a prominent target for cancer imaging and therapy. Currently, radiotracer alpha-[ 11 C]methyl-L-tryptophan ([ 11 C]AMT) is used for PET imaging of the IDO-mediated kynurenine pathway in clinical and preclinical research [223,224]. In two studies, Bosnyak et al evaluated the ability of [ 11 C]AMT to differentiate between meningioma and grade II and grade III gliomas and the prognostic role of the radiotracer, finding that GBM patients with higher pre-treatment tumoral tryptophan uptake, expressed as tumour/cortex SUV-ratios, showed longer survival [225,299].…”

The One Health Consortium: Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Combination With a Checkpoint Inhibitor in Canine Patients With Sporadic High Grade Gliomas

“…Although investigators did not confirm this effect in vivo, this finding may be related to distinct gene expression profiles between long-term established cell lines and tumors in situ. There are multiple active or completed human studies of Indoximod alone and in combination with chemotherapy or immunotherapy for advanced solid malignancies, including brain tumors (38)(39)(40). Newlink Genetics, Corp. has sponsored two companion clinical trials in children (NCT02502708) and adults (NCT02502648) with recurrent or progressive malignant brain tumors to explore safety and tolerability of Indoximod and temozolomide chemotherapy.…”