{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:04:29Z","timestamp":1793045069910,"version":"4.5.0"},"reference-count":43,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"content-version":"unspecified","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,11,15]]},"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Many cancer patients do not obtain clinical benefit from immune checkpoint inhibition. Checkpoint blockade targets T cells, suggesting that tyrosine kinase activity profiling of baseline peripheral blood mononuclear cells may predict clinical outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Here a total of 160 patients with advanced melanoma or non-small-cell lung cancer (NSCLC), treated with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed cell death 1 (anti-PD-1), were divided into five discovery and cross-validation cohorts. The kinase activity profile was generated by analyzing phosphorylation of peripheral blood mononuclear cell lysates in a microarray comprising of 144 peptides derived from sites that are substrates for protein tyrosine kinases. Binary grouping into patients with or without clinical benefit was based on Response Evaluation Criteria in Solid Tumors V.1.1. Predictive models were trained using partial least square discriminant analysis (PLS-DA), performance of the models was evaluated by estimating the correct classification rate (CCR) using cross-validation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The kinase phosphorylation signatures segregated responders from non-responders by differences in canonical pathways governing T-cell migration, infiltration and co-stimulation. PLS-DA resulted in a CCR of 100% and 93% in the anti-CTLA-4 and anti-PD1 melanoma discovery cohorts, respectively. Cross-validation cohorts to estimate the accuracy of the predictive models showed CCRs of 83% for anti-CTLA-4 and 78% or 68% for anti-PD-1 in melanoma or NSCLC, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Blood-based kinase activity profiling for response prediction to immune checkpoint inhibitors in melanoma and NSCLC revealed increased kinase activity in pathways associated with T-cell function and led to a classification model with a highly accurate classification rate in cross-validation groups. The predictive value of kinase activity profiling is prospectively verified in an ongoing trial.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001607","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T13:11:32Z","timestamp":1608729092000},"page":"e001607","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Blood-based kinase activity profiling: a potential predictor of response to immune checkpoint inhibition in metastatic cancer"],"prefix":"10.1136","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8750-5188","authenticated-orcid":false,"given":"Daan P","family":"Hurkmans","sequence":"first","affiliation":[{"name":"Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-8707","authenticated-orcid":false,"given":"Els M E","family":"Verdegaal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-8109","authenticated-orcid":false,"given":"Sabrina A","family":"Hogan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"de Wijn","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lies","family":"Hovestad","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne M A","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Ruijtenbeek","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marij J P","family":"Welters","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"van Brakel","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin A","family":"Basak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-371X","authenticated-orcid":false,"given":"Herbert M","family":"Pinedo","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor H J","family":"Lamers","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harmen J G","family":"van de Werken","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"},{"name":"Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P","family":"Groten","sequence":"additional","affiliation":[{"name":"PamGene International B.V, HH 's-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3649-807X","authenticated-orcid":false,"given":"Reno","family":"Debets","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-9420","authenticated-orcid":false,"given":"Mitchell P","family":"Levesque","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Kapiteijn","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H J","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G J V","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-0354","authenticated-orcid":false,"given":"Sjoerd H","family":"van der Burg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"2025100312353660000_8.2.e001607.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507643"},{"key":"2025100312353660000_8.2.e001607.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504627"},{"key":"2025100312353660000_8.2.e001607.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"2025100312353660000_8.2.e001607.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2025100312353660000_8.2.e001607.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1202947"},{"key":"2025100312353660000_8.2.e001607.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2015.01.003"},{"key":"2025100312353660000_8.2.e001607.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1292"},{"key":"2025100312353660000_8.2.e001607.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705327114"},{"key":"2025100312353660000_8.2.e001607.9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1972"},{"key":"2025100312353660000_8.2.e001607.10","doi-asserted-by":"crossref","DOI":"10.3390\/cancers11060762","article-title":"Differential kinase activation in peripheral blood mononuclear cells from non-small-cell lung cancer patients treated with nivolumab","volume":"11","author":"No\u00e9","year":"2019","journal-title":"Cancers"},{"key":"2025100312353660000_8.2.e001607.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072692"},{"key":"2025100312353660000_8.2.e001607.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2010.04.036"},{"key":"2025100312353660000_8.2.e001607.13","doi-asserted-by":"crossref","first-page":"68599","DOI":"10.18632\/oncotarget.19803","article-title":"Ex vivo multiplex profiling of protein tyrosine kinase activities in early stages of human lung adenocarcinoma","volume":"8","author":"Arni","year":"2017","journal-title":"Oncotarget"},{"key":"2025100312353660000_8.2.e001607.14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801946"},{"key":"2025100312353660000_8.2.e001607.15","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.36"},{"key":"2025100312353660000_8.2.e001607.16","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/cncr.32468","article-title":"Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC)","volume":"126","author":"Bodor","year":"2020","journal-title":"Cancer"},{"key":"2025100312353660000_8.2.e001607.17","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s00262-020-02506-x","article-title":"Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients","volume":"69","author":"Hurkmans","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"2025100312353660000_8.2.e001607.18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2412"},{"key":"2025100312353660000_8.2.e001607.19","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ejca.2016.12.011","article-title":"Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients","volume":"73","author":"Wistuba-Hamprecht","year":"2017","journal-title":"Eur J Cancer"},{"key":"2025100312353660000_8.2.e001607.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00608-2"},{"key":"2025100312353660000_8.2.e001607.21","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01474","article-title":"Biomarkers for clinical benefit of immune checkpoint inhibitor Treatment-A review from the melanoma perspective and beyond","volume":"9","author":"Buder-Bakhaya","year":"2018","journal-title":"Front Immunol"},{"key":"2025100312353660000_8.2.e001607.22","doi-asserted-by":"crossref","first-page":"376","DOI":"10.21037\/atm.2017.06.48","article-title":"Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer","volume":"5","author":"Voong","year":"2017","journal-title":"Ann Transl Med"},{"key":"2025100312353660000_8.2.e001607.23","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw016"},{"key":"2025100312353660000_8.2.e001607.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2017.01.013"},{"key":"2025100312353660000_8.2.e001607.25","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s00262-018-2126-z","article-title":"Pretreatment neutrophil-to-lymphocyte ratio is associated with outcome of advanced-stage cancer patients treated with immunotherapy: a meta-analysis","volume":"67","author":"Jiang","year":"2018","journal-title":"Cancer Immunol Immunother"},{"key":"2025100312353660000_8.2.e001607.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0127"},{"key":"2025100312353660000_8.2.e001607.27","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4466"},{"key":"2025100312353660000_8.2.e001607.28","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0608-y"},{"key":"2025100312353660000_8.2.e001607.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2017.11.123"},{"key":"2025100312353660000_8.2.e001607.30","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.cels.2018.07.001","article-title":"Coral: clear and Customizable visualization of human kinome data","volume":"7","author":"Metz","year":"2018","journal-title":"Cell Syst"},{"key":"2025100312353660000_8.2.e001607.31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40364-017-0093-8","article-title":"Utility of PD-L1 immunohistochemistry assays for predicting PD-1\/PD-L1 inhibitor response","volume":"5","author":"Diggs","year":"2017","journal-title":"Biomark Res"},{"key":"2025100312353660000_8.2.e001607.32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348"},{"key":"2025100312353660000_8.2.e001607.33","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/cdd.2016.35","article-title":"The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade","volume":"23","author":"Yamazaki","year":"2016","journal-title":"Cell Death Differ"},{"key":"2025100312353660000_8.2.e001607.34","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.3"},{"key":"2025100312353660000_8.2.e001607.35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00010"},{"key":"2025100312353660000_8.2.e001607.36","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0841"},{"key":"2025100312353660000_8.2.e001607.37","doi-asserted-by":"publisher","DOI":"10.1038\/nature14011"},{"key":"2025100312353660000_8.2.e001607.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature13954"},{"key":"2025100312353660000_8.2.e001607.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.02.001"},{"key":"2025100312353660000_8.2.e001607.40","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0283"},{"key":"2025100312353660000_8.2.e001607.41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.7.4262"},{"key":"2025100312353660000_8.2.e001607.42","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21409"},{"key":"2025100312353660000_8.2.e001607.43","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod55.1.207"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-001607","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T19:35:43Z","timestamp":1759520143000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-001607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,12,22]]},"published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10.1136\/jitc-2020-001607"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-001607","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12]]}}}