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Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

ABSTRACT: Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

PROVIDER: PRJNA498500 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8112650_1.fastq.gz	Fastqsanger.gz
	SRR8112650_2.fastq.gz	Fastqsanger.gz
	SRR8112660_1.fastq.gz	Fastqsanger.gz
	SRR8112660_2.fastq.gz	Fastqsanger.gz
	SRR8112670_1.fastq.gz	Fastqsanger.gz

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Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

Project description:Glioblastoma is the most common primary malignant brain tumor in adults and associated with poor survival. Standard-of-care chemotherapy and radiation confer a median overall survival of under two years. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical PD-1 blockade alone (hazard ratio = 0.39; P = 0.04, log-rank test). Neoadjuvant PD-1 blockade was associated with upregulation of T cell and interferon-γ-related genes, but downregulation of cell cycle related genes within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 (PD-L1) in the tumor microenvironment was observed more frequently in the neoadjuvant group than in tumors obtained from patients treated only in the adjuvant setting. Similarly, neoadjuvant pembrolizumab was associated with clonal T cell expansion and the overlap of T cell receptors between tumor and blood, decreased PD-1 expression in T cells and a decreasing peripheral monocytic population. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor. This trial was registered with ClinicalTrials.gov under the identifier NCT02852655 (https://clinicaltrials.gov/ct2/show/NCT02852655).

2018-12-05 | GSE121810 | GEO

Neoadjuvant intratumoral immunotherapy with cowpea mosaic virus induces local and systemic antitumor efficacy in canine mammary cancer patients.

Project description:This study evaluated the efficacy, safety, and effects on treated and untreated tumors, and clinical impact of neoadjuvant intratumoral empty cowpea mosaic virus (eCPMV) immunotherapy in CMC patients.

2023-09-12 | GSE242689 | GEO

Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort

Project description:Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue in an additional 25 patients with surgically-accessible recurrent glioblastoma. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.

2024-09-24 | GSE264695 | GEO

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Project description:Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

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Intratumoral heterogeneity and longitudinal changes in gene expression predict differential drug sensitivity in newly diagnosed and recurrent glioblastoma

Project description:We investigated longitudinal transcriptomic patterns associated with glioblastoma (GB) recurrence by integrative approach utilizing multisampling strategy, RNA sequencing and complementary investigations of tumor tissues and GB stem cells. In total, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent GBs were analyzed in parallel with 27 primary cultures of GB stem cells. We found that intratumoral transcriptomic heterogeneity is an intrinsic characteristic that is conserved in newly diagnosed and recurrent GBs and captured in GB stem cells. We revealed a high degree of concordance between GB tumor tissues and stem cells in the longitudinal transcriptomic changes associated with tumor recurrence. We used gene expression data to model the efficacy of 130 anti-cancer drugs. For the recurrent tumor tissues and isolated GB stem cells we showed dramatically reduced simulated sensitivities to the first line chemotherapeutic temozolomide. In turn, several therapeutics including immune checkpoint inhibitors were predicted to be more effective in the recurrence setting. Our results strongly suggest that the spectrum of potentially effective drugs may differ between newly diagnosed and recurrent glioblastomas and provides a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent GB.

2020-03-01 | GSE139533 | GEO

Neoadjuvant intratumoral immunotherapy with cowpea mosaic virus induces local and systemic antitumor efficacy in canine mammary cancer patients.

Project description:Neoadjuvant intratumoral immunotherapy with cowpea mosaic virus induces local and systemic antitumor efficacy in canine mammary cancer patients.

| PRJNA1014121 | ENA

Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor: results from PNOC005

Project description:Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model. MV-NIS given intratumorally or via repeat intrathecal dosing was safe. MV-NIS prolonged survival in murine models but did not demonstrate additive benefit with ICI. No changes in tumor-infiltrating immune-cell composition or activation were observed in response to MV-NIS treatment; however, MV-NIS induced local expression of neutralizing antibodies, complement cascade, and phagocytosis-related genes.

2025-04-17 | GSE294901 | GEO

Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor: results from PNOC005

2025-04-17 | GSE294899 | GEO

Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma

Project description:Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4) from the CIAO clinical trial (NCT03144778). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent patient cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction of intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in patient tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PD-L1 immune checkpoint blockade, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of anti-tumor immunity and promotes immunotherapy resistance.

2025-09-09 | GSE307471 | GEO

Identification of recurrent GBM patients that may benefit from Bevacizumab and CCNU: A report from the BELOB trial by the Dutch Neurooncology Group

Project description:The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva; a humanized monoclonal antibody against circulating VEGF-A) when added to CCNU chemotherapy in recurrent GBM patients. In this study, we have performed gene expression profiling (DASL and RNA-seq) on formalin fixed, paraffin embedded (FFPE) tumor material from patients treated within the BELOB trial to identify recurrent GBM patients who benefit most from combined beva/CCNU treatment. We first extensively validate the use of FFPE tissues for expression profiling on both DASL and RNA-seq. Our data show that tumors assigned to IGS-18 or ‘classical’ GBMs show a significant benefit in progression free survival (PFS) and a trend towards benefit in overall survival (OS) from beva+CCNU treatment; other subtypes do not show such benefit. In particular, expression of FMO4 and OSBPL3 were associated with treatment response. All molecular glioma subtypes are evenly distributed along the different study arms and the improved outcome in the beva/CCNU arm therefore is not explained by an uneven distribution of prognostically favorable subtypes. Analysis of RNA-seq data highlighted genetic changes, including mutations, gene fusions (and identification of the exact genomic breakpoint), and copy number changes (albeit with limited resolution) within this well-defined cohort of tumors. When validated in an independent dataset, the predictive markers identified in this study will allow selection of recurrent GBM patients that benefit from beva+CCNU treatment.

2016-01-19 | GSE72951 | GEO

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