Newly-diagnosed IDHwt MGMT unmethylated glioblastoma patients treated with standard radiation, nivolumab, and BMS-986205 [bulk RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1212513 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32043629.fastq.gz | Fastqsanger.gz | |||
| SRR32043631.fastq.gz | Fastqsanger.gz | |||
| SRR32043634.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 [scRNA-seq]
| PRJNA1212512 | ENA
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: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
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
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:BackgroundAddition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.MethodsPatients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS.ResultsA total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively.ConclusionsThe study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.
| S-EPMC9825306 | biostudies-literature
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
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 | GSE292046 | GEO