Brandyn Castro

Patient Demographics of those enrolled in the trial

Purpose: We conducted a phase I trial to evaluate radiotherapy (RT) and nivolumab with the further addition of an indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitor (BMS-986205) in newly diagnosed patients with glioblastoma (GBM) IDH wild-type. Patients and Methods: In the current study, there were two primary cohorts of individuals. Cohort A included patients with O6-methylguanine-DNA methyltransferase (MGMT)–unmethylated GBM who received RT with concurrent and adjuvant nivolumab with escalating BMS-986205 doses. Cohort B included patients with MGMT-methylated GBM who received BMS-986205 at 25 mg daily with RT, nivolumab, and temozolomide (TMZ) followed by adjuvant TMZ. Patient outcomes were correlated with flow cytometric, transcriptome, general metabolite, and microbial metabolite analyses. Results: The treatments for both cohorts were moderately safe and tolerable. The treatment-emergent adverse events (TEAE) were mostly related to RT, TMZ, or the underlying disease and tumor progression. In cohort A, serious adverse events and TEAEs were predominantly lower grade, with no differences between the IDO1 enzyme inhibitor dosing cohorts. Dose-limiting toxicities reflected by increased transaminases (grade 3) were observed in two and three patients at the 50 and 100 mg levels of BMS-986205, respectively, with malaise observed in the 50 mg arm only. The 50 mg daily schedule was established as the recommended phase II dose (RP2D) in combination with RT and nivolumab. A number of exploratory correlative studies were also conducted. Conclusions: This single-arm, small phase I trial establishes a safety profile and RP2D for RT in combination with nivolumab and BMS-986205 for newly diagnosed patients with MGMT-unmethylated GBM (ClinicalTrials.gov: NCT04047706).

Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

Supplementary Figure from Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma

Supplementary Figure from Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma

Supplementary Figure from Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma