Ontology highlight
ABSTRACT:
PROVIDER: PRJEB47144 | ENA |
REPOSITORIES: ENA
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Project description:Gene profiling analysis to evaluate pre- and post-immune checkpoint therapy with tremelimumab (anti-CTLA-4) plus durvalumab (anti-PD-L1) as neoadjuvant treatment prior to radical cystectomy in MICB were analyzed using customized 749- gene Nanostring panel
2022-11-01 | GSE140278 | GEO
Project description:Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n=26), or durvalumab and trametinib given concomitantly (cohort B, n=20) or sequentially (cohort C, n=22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.
2020-09-24 | GSE158403 | GEO
Project description:Only a subset of patients responds to immune checkpoint blockade in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T cell infiltration, and T cell receptor (TCR) signatures in regressing tumors compared to tumors exhibiting no response to anti-PD-L1 treatment. We found that CD8+ T cell tumor infiltration corresponded to response to treatment, and that anti-PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. TCR sequence data suggest that an anti-PD-L1-mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.
2021-04-20 | GSE172320 | GEO
Project description:Only a subset of patients responds to immune checkpoint blockade in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T cell infiltration, and T cell receptor (TCR) signatures in regressing tumors compared to tumors exhibiting no response to anti-PD-L1 treatment. We found that CD8+ T cell tumor infiltration corresponded to response to treatment, and that anti-PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. TCR sequence data suggest that an anti-PD-L1-mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.
2021-04-17 | GSE172239 | GEO
Project description:Intracranial B16 melanoma tumors isolated from C57Bl6 mice were analyzed by mRNAseq. Four experimental groups were analyzed: (1) Mice with intracranial tumors receiving IgG; (2) Mice with intracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy; (3) Mice with intracranial plus extracranial tumors receiving IgG; (4) Mice with intracranial plus extracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy. Taggart et al., PNAS 2018;
2018-02-01 | GSE109485 | GEO
Project description:Response to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.
2015-03-16 | GSE65503 | GEO
Project description:KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of tumors associated with resistance to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA-damage response (DDR)-based therapies, the impact of KEAP1 alterations remains unknown. Here we demonstrate that KEAP1/NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi) particularly in the setting of increased replication stress associated with LKB1 loss. ATRis show enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient NSCLC models and synergy combined with gemcitabine. ATRi also enhances antitumor immunity and helps mitigate the immunosuppressed phenotype of LKB1 and/or KEAP1-deficient tumors. Finally, in the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1/NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as useful biomarkers for predicting response to ATRi combination regimens.
2025-06-15 | E-MTAB-15235 | biostudies-arrayexpress
Project description:Gene expression in 10 skin metastases from a patient with melanoma who had been treated with anti-PD-1 (Nivolumab) therapy was measured. Differences in gene expression between the lesions which responded to the treatment (n = 6) and the lesions which progressed (n = 4) were analyzed. Expression of certain genes associated with the extracellular matrix and with neutrophil function was found to be higher in the metastases which progressed. Insight into the biology governing response to immunotherapy may lead to improved rationally designed therapies, and to biomarkers for selecting patients who are more likely to benefit from these treatments.
2017-02-14 | GSE79691 | GEO
Project description:Purpose: Use RNA-seq to characterize the anti-tumor immune response induced by ALPN-202 and compare to that of anti-PD-L1 treatment alone. Methods: mRNA was isolated from MC38/hPD-L1 tumors 72 hours after a single dose of ALPN-202 (n=4), anti-PD-L1 mAb (durvalumab) (n=4), or Fc control (n=4). Results: ALPN-202 treatment resulted in elevated expression of multiple T cell, NK cell, myeloid cell genes. Additionally, there was a strong increase in genes commonly associated with a proinflammatory response including cytokines, chemokines and surface markers. Conclusions: ALPN-202 treatment resulted in a strong anti-tumor immune response that was more potent than that generated by blockade of PD-L1 alone.
2022-02-10 | GSE161244 | GEO
Project description:Cholangiocarcinoma (CCA) shows limited response to systemic treatments including immunotherapy. We initiated an open-label phase II clinical trial testing bevacizumab (anti-VEGF-A) plus tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) in patients with primary liver cancer. Exceptional responses were observed in patients with CCA that were accompanied with moderate to severe, yet manageable immune-related events in the majority of patients. Correlative studies using paired PBMC and serum samples demonstrated a proinflammatory cytokine profile, reinvigoration of precursor exhausted CD8+ T cells, and expansion of regulatory T cell and non-classical monocyte subsets. We utilized subcutaneous, orthotopic as well as plasmid-induced murine CCA models to better understand how anti-VEGF-A enhances anti-tumor immunity induced by anti-CTLA4 plus anti-PD-L1. We describe a novel multi-modal mechanism of how anti-VEGF-A therapy enhances immune checkpoint inhibitor-induced immune responses. The treatment effect was dependent on an increase in tumor infiltrating B cells and IL-12 causing Treg rewiring towards fragile and unstable states. Using a mouse model that genetically ablates VEGFR2 expression on Tregs, we show that the VEGF /VEGFR2 axis on Tregs contributes to the pro-tumoral function of Tregs and supports tumor progression in a syngeneic CCA model. This study provides clinical evidence that simultaneously targeting three immunosuppressive axes, namely VEGF-A, CTLA-4 and PD-L1, can elicit strong anti-tumor immunity to potentiate CCA regression and merits broader evaluation in other cancers.
2025-03-14 | GSE249974 | GEO