F3506e87-4bfc-4be6-b070-ecd8d69441b7 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001005973 | EGA |
REPOSITORIES: EGA
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Project description:We are interested in inter-individual variation in transcriptional response to immune checkpoint blockade. We have analysed poly A purified RNA expression from CD8 T cells (297 transcriptomes in total) isolated from metastatic melanoma patients (n=106) prior to and during treatment with either single agent (Pembrolizumab) or combination (Ipilimumab/ Nivolumab) immune checkpoint blockade. We compare expression at different stages of treatment and additionally contrast this with that from healthy controls (n=68).
| EGAS00001004081 | EGA
Project description:In this comprehensive study, the authors have developed concise models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 Immune Checkpoint Blockade (ICB) treatment in individual tumors. It's important to note that their validation was performed in smaller, independent cohorts, constrained by data availability. The authors have developed two Logistic Regression based models for Ipilimumab treated and Ipilimumab naive patients with metastatic melanoma. The main predictive features for the Ipilimumab treated patients are MHC-II HLA, LDH at treatment initiation and the presence of lymph node metastases (LN met), chosen using forward selection methodology. The main predictive features for the Ipilimumab naive patients are tumor heterogeneity, tumor ploidy and tumor purity, chosen using forward selection methodology.
Please note that in these models, the output ‘1’ means progressive disease (PD) and ‘0’ means non-PD. The original GitHub repository can be accessed at https://github.com/vanallenlab/schadendorf-pd1
2023-11-17 | MODEL2310150001 | BioModels
Project description:Resistance to immune checkpoint inhibitors (ICI) in cancer patients is not fully understood and predictive biomarkers are lacking. MELANFα (NCT03348891) is an open-label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab; monotherapy: pembrolizumab or nivolumab). In this study we collected blood from patients taken at baseline (week0) and 6 weeks after treatment initiation (week6), isolated peripheral blood monuclear cells and assessed the impact of treatment systemic immune responses to identify potential markers of response/resistance.
2025-03-23 | GSE289084 | GEO
Project description:Raw sequencing data for magnetically-sorted CD8+ T cells and monocytes from the peripheral blood of eight individuals receiving immune checkpoint blockade (either combination ipilimumab/nivolumab, n=4; or single-agent pembrolizumab, n=4) for the treatment of metastatic melanoma. Samples were taken immediately before the first treatment and 21 days post-treatment. Cells were selected based on positivity for CD8 or CD14 and sorted into single cells using the Chromium (10X Genomics) droplet-based system. Gene expression and V(D)J libraries were prepared in accordance with published protocols before sequencing Illumina HiSeq4000. Analysis of CD8 T cell gene expression and V(D)J features can be found in the associated publication (DOI https://doi.org/10.1101/2020.11.15.383786).
| EGAS00001005507 | EGA
Project description:While immune checkpoint blockade therapies are commonly utilized during the course of metastatic cancer treatment, much remains unknown regarding the mechanisms underlying individual therapies. CD8+ T cells from 8 patients that had been treated with either adjuvant Ipilimumab or Nivolumab were compared to assess immunological differences between the therapies. CD8+ T cells from patients that had received Ipilimumab exhibited higher cytotoxic gene expression and pathway enrichment than those from patients that had received Nivolumab. Cytotoxic activity was especially driven by cluster 3 in both groups, with the proportion of CD8+ T cells in the cluster expanding significantly in Ipilimumab patients over the course of treatment, in contrast to Nivolumab patients where this pattern was not seen. This data suggests that, on the CD8+ T cell level, Ipilimumab and Nivolumab exhibit mechanistic differences that are driven by cytotoxic genes and pathways.
2024-10-24 | GSE268364 | GEO
Project description:Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which resulted in prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior standard chemotherapy but no prior immune checkpoint inhibitor. Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. In conclusion, the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.
2026-03-01 | GSE316402 | GEO
Project description:Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which resulted in prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior standard chemotherapy but no prior immune checkpoint inhibitor. Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. In conclusion, the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.
2026-03-01 | GSE317605 | GEO
Project description:<p>Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.</p> <p>We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.</p> <p>Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.</p>
| phs001041 | dbGaP
Project description:Immune checkpoint blockade has limited efficacy in microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer. Preclinical models have demonstrated the use of radiation to activate the innate immune response and stimulate responsiveness to immune checkpoint blockade. Here, we describe a Phase 2 trial of radiation therapy combined with combined anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) antibodies in MSS CRC and PDAC. In the per protocol analysis disease control rate was 37% (10/27) in CRC and 29% (5/17) in PDAC with an overall response rate of 15% (4/27) and 18% (3/17), respectively. Whole exome and RNA sequencing of biopsies from 17 patients revealed low tumor mutational burden in all tumors, but a notable upregulation of interferon stimulated genes with concordant high expression of multiple repeat RNA transcripts in responders. Altogether, this study provides foundational human proof of concept of radiation with combination immune checkpoint blockade therapy in otherwise immunotherapy resistant cancers.
2021-07-06 | GSE179351 | GEO
Project description:<p>Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (<i>B2M</i>), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified <i>B2M</i> aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping <i>B2M</i>, and absence of tumor-specific <i>B2M</i> protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that <i>B2M</i> LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of <i>B2M</i> was found only in nonresponders. We also found evidence for association of LOH overlapping <i>IFNGR1</i> with poorer overall survival exclusively in the anti-PD1 cohort. Thus, <i>B2M</i> loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.</p>
| phs001427 | dbGaP