Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1212512 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32043746.fastq.gz | Fastqsanger.gz |
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Project description: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).
2025-06-02 | GSE287372 | GEO
Project description: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).
2025-06-02 | GSE287371 | GEO
Project description:Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]
| PRJNA1212513 | ENA
Project description:Background: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCRs) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T cell immunity. Methods: We conducted a phase I/II single institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), an oral CCR2/5 inhibitor BMS-813160 and nivolumab for four 28-day cycles as a neoadjuvant therapy for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase 2 dose (RP2D) of BMS-813160 was established in the standard 3+3 design. Primary end points were safety and objective response rate (ORR). Secondary end points included resection rate, progression-free survival (PFS) and overall survival (OS). Results: 8 patients were treated with GnP alone (control arm) and 31 patients (29 response evaluable) were treated at RP2D. No grade 3 or 4 toxicities attributed to nivolumab or BMS-813160 were identified. After all 4 cycles of study treatment (N=26), ORR was 35.7%, 16.7% among BR- and LA-PDAC patients, compared to 0% of control arm patients. 78.6% BR- and 16.7% of LA-PDAC patients who completed study treatment underwent surgical resection. For intent-to-treat analyses, BR-PDAC patients had a mPFS and mOS of 14.6 and 20.4 months respectively; and LA-PDAC patients had a mPFS and mOS of 14.7 and 17 months respectively. Single cell RNAseq analysis showed enhanced proliferating CD4 and CD8 T cells and gene signatures indicative of effector function. Conclusions: Neoadjuvant BMS-813160/nivolumab/GnP was well tolerated and appears to achieve higher ORR and resectability than historical data, warranting a larger randomized phase II study.
2025-03-11 | GSE288533 | GEO
Project description:Abstract BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination. METHODS Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs. RESULTS Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up >12 months) will be available at the time of the meeting. CONCLUSIONS Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.
| S-EPMC8598682 | biostudies-literature
Project description:Neoadjuvant BMS-813160, nivolumab, gemcitabine and nab-paclitaxel for pancreatic cancer
| PRJNA1218232 | ENA
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2016-05-15 | E-MTAB-3218 | biostudies-arrayexpress
Project description:Expression profiling of tumor samples obtained during CA209-038 (ClinicalTrials.gov Identifier: NCT01621490). The purpose of this study is to evaluate pharmacodynamic changes of nivolumab and nivolumab in combination with ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced). Samples are rumor core needle biopsies obtained at trial enrolment (i.e. Screen) and/or at Cycle 1 Day 29 (i.e.Week 4) from Subjects With Advanced Melanoma (Unresectable or Metastatic) treated with nivolumab (BMS-936558,MDX-1106) 3 mg/kg solution intravenously every 2 weeks on Bristol-Myers Squibb clinical trial protocol CA209-038 Part 1 . Cohort 2 patients have progressed on anti-CTLA4 (ipilimumab) monoclonal antibody therapy. Values are from an interim lock of the trial data in July 2014. Best overall response (BOR) was defined using RECIST 1.1 criteria: tumor assessments between date of first dose and the date of first objectively documented progression, or the date of non-missing subsequent anti-cancer therapy (whichever occurs first) were used to derive BOR. MPCT is Maximum reduction in tumor size (index lesions only) up to first progression, and is the value typically shown on a waterfall plot.
2022-01-01 | E-MTAB-4030 | biostudies-arrayexpress
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2016-05-15 | E-MTAB-3219 | biostudies-arrayexpress
Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.
2019-08-20 | PXD007193 | Pride