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Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]

ABSTRACT: Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]

PROVIDER: PRJNA1212513 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR32043629.fastq.gz	Fastqsanger.gz
	SRR32043631.fastq.gz	Fastqsanger.gz
	SRR32043634.fastq.gz	Fastqsanger.gz

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Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205

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).

2026-05-06 | GSE300413 | GEO

Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [scRNA-seq]

2025-06-02 | GSE287372 | GEO

Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]

2025-06-02 | GSE287371 | GEO

Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [scRNA-seq]

Project description:Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [scRNA-seq]

| PRJNA1212512 | ENA

CTIM-12. A PHASE 1 TRIAL OF IMMUNORADIOTHERAPY WITH THE IDO ENZYME INHIBITOR (BMS-986205) AND NIVOLUMAB IN PATIENTS WITH NEWLY DIAGNOSED MGMT PROMOTER UNMETHYLATED IDHwt GLIOBLASTOMA

Project description: Not available

| S-EPMC8598682 | biostudies-literature

Epigenetic evolution of IDHwt glioblastomas

Project description:Although the genetic evolution of IDH-wildtype glioblastomas has extensively been investigated, limited studies have addressed the epigenetic evolution. Understanding the epigenetic evolution is particularly relevant as demethylation of the MGMT promoter may form a means to treatment resistance. Methods We generated whole genome DNA methylation data of 64 matched primary-recurrent samples from IDH-wildtype glioblastoma patients. Data were combined with three publicly available datasets into a final cohort consisting of 418 samples. In the combined dataset, we determined change in genome-wide DNA-methylation. MGMT promoter methylation was defined using the MGMT-STP27 algorithm. CoxPH regression was used to investigate the impact of identified changes on survival. Results Our analysis demonstrates that the methylome of IDH-wildtype glioblastomas is highly stable. Changes that do occur can mostly be allocated to differences in tumor purity. Conversion from a MGMT promoter methylated to unmethylated status at progression occurred infrequently, but significantly more often than the converse. Conversion was associated with poorer overall and progression-free survival compared to those that remained MGMT methylated. Similar to previously reported, MGMT promoter methylation status was significantly associated with overall-, progression-free and post-recurrence survival. Despite this large survival difference, very few CpGs were co-methylated with the MGMT methylation status. Of these, the vast majority lied within the MGMT gene body and were inversely correlated with MGMT promoter methylation status. Conclusions The methylome of IDH-wildtype glioblastomas is highly stable at tumor progression. This stability is also present in the MGMT promoter.

2026-03-19 | GSE305349 | GEO

Plasma Mouse LC-MSMS - Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival

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

Neoadjuvant BMS-813160, nivolumab, gemcitabine and nab-paclitaxel for pancreatic cancer

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

Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial.

Project description: Not available

| S-EPMC9825306 | biostudies-literature

Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase I trial [RNA-seq]

Project description:Glioblastoma is a devastating disease with a prognosis of less than 24 months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of a phase 1 clinical trial (NCT04015700) to assess the safety and efficacy of GNOS-PV01, a personalized DNA vaccine platform, in patients with newly diagnosed MGMT unmethylated glioblastoma following surgery and radiation. Results show GNOS-PV01 is able to safely immunize against up to 40 neoantigens per patient (range 17-40) with neoantigen-specific T cell responses detectable in all evaluated subjects post-vaccination (7 of 7). Furthermore, we developed a novel T cell enrichment method for single nuclei RNA-sequencing to transcriptionally characterize tumor-infiltrating T cells after vaccination. Survival outcomes were encouraging with one-third of vaccinated patients (3 of 9) alive beyond 24 months. Moreover, induction of neoantigen-specific responses was associated with subsequent reactivity to PD-1 blockade therapy.

2026-02-10 | GSE292045 | GEO

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