4 results on '"Mateo Sokac"'
Search Results
2. Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma
- Author
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Jesper Geert Pedersen, Mateo Sokac, Boe Sandahl Sørensen, Adam Andrzej Luczak, Ninna Aggerholm-Pedersen, Nicolai Juul Birkbak, Trine Heide Øllegaard, and Martin Roelsgaard Jakobsen
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immunotherapy ,melanoma ,liquid biopsies ,inflammatory cytokines ,PD-1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40–60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma. Methods: We studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis. Results: Interestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034–0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS. Conclusions: In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response.
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- 2022
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3. 27 Cytokine signature of PD-1, CXCL10, and TNF-alpha predicts response to nivolumab and ipilimumab
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Martin R. Jakobsen, Trine Heide Øllegaard, Jesper Pedersen, Mateo Sokac, and Nicolai Juul Birkbak
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Melanoma ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Ipilimumab ,Pembrolizumab ,medicine.disease ,Interleukin 10 ,Cytokine ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,CXCL10 ,Nivolumab ,business ,Survival analysis ,RC254-282 ,medicine.drug - Abstract
BackgroundCheckpoint inhibitors have significantly improved treatment of metastatic melanoma. Yet, 40–60% of the patients do not achieve a long-term benefit from such immunotherapy. Thus, there is an urgent need to identify biomarkers that can predict response to immunotherapy to guide patients for the best possible treatment. Here, we evaluate an unsupervised machine learning approach to identify potential cytokine signatures from liquid biopsies that predict response to immunotherapy in melanoma.MethodsBlood samples were drawn from 74 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab/ipilimumab or pembrolizumab between August 2017 – July 2019 at Aarhus University Hospital, Denmark. Blood samples were tested for plasma levels of PD-1, PD-L1, IFN-beta, IFN-gamma, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNF-alpha by Meso Scale ELISA assays. Healthy controls were used to compare general cytokine levels in plasma. A bioinformatic workflow consisting of Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis was applied to define clusters based on the cytokine profile, followed by survival analysis of the clusters.ResultsUMAP analysis demonstrated that the cytokine profile at baseline was similar for healthy controls and patients, regardless of treatment. Upon treatment initiation, the cytokine profile changed in a treatment-dependent way to be significantly different between patient groups. Clustering defined by the cytokine profile measured early during treatment in nivolumab/ipilimumab treated patients identified two clusters associated with superior progression-free survival (PFS) (log-rank p=0.018). We identified that these cluster were characterized by significantly higher levels of PD-1, CXCL10, and TNF-alpha. UMAP analysis of the cytokine level as fold change over baseline level, confirmed that nivolumab/ipilimumab patients with superior PFS were characterized by higher levels of PD-1, CXCL10, and TNF-alpha. Cox regression analysis revealed high fold change of PD-1 as a strong predictor for superior PFS (HR=0.29; 95% CI 0.12–0.66; p=0.0032). However, a similar cytokine profile was not associated to superior PFS in patients receiving pembrolizumab, suggesting that the cytokine signature is specific for nivolumab/ipilimumab treatment.ConclusionsUsing unsupervised machine learning we identified a cytokine signature of high PD-1, CXCL10, and TNF-alpha to be associated with superior PFS in advanced-stage melanoma patients treated with nivolumab/ipilimumab but not pembrolizumab, with high fold change of PD-1 being a strong individual predictor for PFS.AcknowledgementsWe thank the medical laboratory technicians who collected blood samples and the patients who participated in the study.Ethics ApprovalThe study was approved by Central Denmark Region Committees on Biomedical Research Ethics, approval number 1-10-72-374-15.
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- 2021
4. Computational Analysis Reveals the Temporal Acquisition of Pathway Alterations during the Evolution of Cancer
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Johanne Ahrenfeldt, Ditte S. Christensen, Mateo Sokač, Judit Kisistók, Nicholas McGranahan, and Nicolai J. Birkbak
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metastasis ,cancer evolution ,bioinformatics ,cancer biology ,cancer genomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Cancer metastasis is the lethal developmental step in cancer, responsible for the majority of cancer deaths. To metastasise, cancer cells must acquire the ability to disseminate systemically and to escape an activated immune response. Here, we endeavoured to investigate if metastatic dissemination reflects acquisition of genomic traits that are selected for. We acquired mutation and copy number data from 8332 tumours representing 19 cancer types acquired from The Cancer Genome Atlas and the Hartwig Medical Foundation. A total of 827,344 non-synonymous mutations across 8332 tumour samples representing 19 cancer types were timed as early or late relative to copy number alterations, and potential driver events were annotated. We found that metastatic cancers had a significantly higher proportion of clonal mutations and a general enrichment of early mutations in p53 and RTK/KRAS pathways. However, while individual pathways demonstrated a clear time-separated preference for specific events, the relative timing did not vary between primary and metastatic cancers. These results indicate that the selective pressure that drives cancer development does not change dramatically between primary and metastatic cancer on a genomic level, and is mainly focused on alterations that increase proliferation.
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- 2022
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