Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]
Improving immunotherapeutic efficacy for patients with glioblastoma (GBM) has been suggested to be limited by a number of factors including indoleamine 2,3 dioxygenease 1 (IDO; IDO1); an enzyme that converts L-tryptophan (Trp) into L-kynurenine (Kyn). Here, we report the results of a first-in-human phase 1 trial for 12 patients with newly-diagnosed IDHwt MGMT unmethylated GBM treated with standard radiation, nivolumab, and BMS-986205 – the latter being a potent IDO1 enzyme inhibitor. The treatment regimen was found to be safe and tolerable when administered at 50mg. Treated patients experienced decreased L-kynurenine levels without changes in L-tryptophan. No other kynurenine-pathway metabolites were altered while on treatment. The median overall survival (OS) was 11.5 months for all patients, with 4 individuals alive at =28 months, and 2 patients alive at 5 years post-diagnosis. Analysis of resected tumor at the time of first recurrence revealed intratumoral IDO1 expression to be primarily enriched in myeloid lineage cells. Higher systemic levels of naïve and early effector CD8+ T cells, higher systemic levels of microbial-derived aryl-lactates, lower systemic levels of microbial-derived aryl acetates, higher levels of fecal-derived Massilioclostridium coli, GGB3819-SGB5184, Dysosmobacter welbionis, Phocaeicola plebeius, an age of <65 years old, and patients who underwent subtotal but not gross total tumor resection, were significantly more likely to live past 28 months while on treatment. This study provides a biological rationale for use of RT, PD-1 mAb, and IDO1 enzyme inhibitor treatment in temodar naïve GBM patients who survive well after 2 years while on treatment (ClinicalTrials.gov: NCT04047706). Overall design: To determine the gene expression regulatory effects of combined therapy evaluated in current clinical trial on peripheral blood leukocytes (PBLs), blood samples were collected from newly diagnoased GBM patients at baseline and different treatment stages during the trial. PBLs were isolated and subject to bulk RNA-Seq analysis.