{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T23:42:06Z","timestamp":1794440526763,"version":"4.9.1"},"reference-count":64,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"content-version":"unspecified","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K99\/R00 CA230201-01"],"award-info":[{"award-number":["K99\/R00 CA230201-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA175732-01"],"award-info":[{"award-number":["R01 CA175732-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,5,20]]},"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Inflammatory mediators, including acute phase reactants and cytokines, have been reported to be associated with clinical efficacy in patients with melanoma and other cancers receiving immune checkpoint inhibitors (ICI). Analyses of patient sera from three large phase II\/III randomized ICI trials, one of which included a chemotherapy arm, were performed to assess whether baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6) or neutrophil\/lymphocyte (N\/L) ratios were prognostic or predictive.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Patients and methods<\/jats:title>\n                  <jats:p>Baseline and on-treatment sera were analyzed by multiplex protein assays from immunotherapy-na\u00efve patients with metastatic melanoma randomized 1:1 on the Checkmate-064 phase II trial of sequential administration of nivolumab followed by ipilimumab or the reverse sequence. Baseline sera, and peripheral blood mononuclear cells using automated cell counting, were analyzed from treatment-na\u00efve patients who were BRAF wild-type and randomly allocated 1:1 to receive nivolumab or dacarbazine on the phase III Checkmate-066 trial, and from treatment-na\u00efve patients allocated 1:1:1 to receive nivolumab, ipilimumab or both ipilimumab and nivolumab on the phase III Checkmate-067 trial.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Higher baseline levels of IL-6 and the N\/L ratio, and to a lesser degree, CRP were associated with shorter survival in patients receiving ICI or chemotherapy. Increased on-treatment levels of IL-6 in patients on the Checkmate-064 study were also associated with shorter survival. IL-6 levels from patients on Checkmate-064, Checkmate-066 and Checkmate-067 were highly correlated with levels of CRP and the N\/L ratio.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>IL-6, CRP and the N\/L ratio are prognostic factors with higher levels associated with shorter overall survival in patients with metastatic melanoma receiving ICI or chemotherapy in large randomized trials. In a multi-variable analysis of the randomized phase III Checkmate-067 study, IL-6 was a significant prognostic factor for survival.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-000842","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T06:35:19Z","timestamp":1592980519000},"page":"e000842","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":234,"title":["Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct01783938","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01721772","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01844505","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03999749","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Andressa S","family":"Laino","sequence":"first","affiliation":[{"name":"Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6328-8107","authenticated-orcid":false,"given":"David","family":"Woods","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Vassallo","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhong","family":"Qian","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tang","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Wind-Rotolo","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Weber","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,6,23]]},"reference":[{"key":"2025100315024287000_8.1.e000842.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.797"},{"key":"2025100315024287000_8.1.e000842.2","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1097\/CMR.0b013e3283550aa5","article-title":"Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma","volume":"22","author":"Hoejberg","year":"2012","journal-title":"Melanoma Res"},{"key":"2025100315024287000_8.1.e000842.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.1978"},{"key":"2025100315024287000_8.1.e000842.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-009-0818-8"},{"key":"2025100315024287000_8.1.e000842.5","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/1878-0261.12433","article-title":"Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells","volume":"13","author":"Mohapatra","year":"2019","journal-title":"Mol Oncol"},{"key":"2025100315024287000_8.1.e000842.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.003"},{"key":"2025100315024287000_8.1.e000842.7","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.molonc.2014.05.008","article-title":"Interleukin-6 drives melanoma cell motility through p38\u03b1-MAPK-dependent up-regulation of WNt5a expression","volume":"8","author":"Linnskog","year":"2014","journal-title":"Mol Oncol"},{"key":"2025100315024287000_8.1.e000842.8","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0030"},{"key":"2025100315024287000_8.1.e000842.9","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.lungcan.2019.03.014","article-title":"Advanced NSCLC patients with high IL-6 levels have altered peripheral T cell population and signaling","volume":"131","author":"Rice","year":"2019","journal-title":"Lung Cancer"},{"key":"2025100315024287000_8.1.e000842.10","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2446"},{"key":"2025100315024287000_8.1.e000842.11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2353"},{"key":"2025100315024287000_8.1.e000842.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.03.009"},{"key":"2025100315024287000_8.1.e000842.13","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2018-4957"},{"key":"2025100315024287000_8.1.e000842.14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-703751"},{"key":"2025100315024287000_8.1.e000842.15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-363390"},{"key":"2025100315024287000_8.1.e000842.16","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13045-016-0309-7","article-title":"Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn's disease: a case report","volume":"9","author":"Uemura","year":"2016","journal-title":"J Hematol Oncol"},{"key":"2025100315024287000_8.1.e000842.17","doi-asserted-by":"publisher","DOI":"10.1177\/1078155217745144"},{"key":"2025100315024287000_8.1.e000842.18","doi-asserted-by":"publisher","DOI":"10.3109\/07853890009011772"},{"key":"2025100315024287000_8.1.e000842.19","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-18233-w","article-title":"The impact of elevated C-reactive protein level on the prognosis for oro-hypopharynx cancer patients treated with radiotherapy","volume":"7","author":"Katano","year":"2017","journal-title":"Sci Rep"},{"key":"2025100315024287000_8.1.e000842.20","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-12703-x","article-title":"Biomarkers of inflammation and breast cancer risk: a case-control study nested in the EPIC-Varese cohort","volume":"7","author":"Agnoli","year":"2017","journal-title":"Sci Rep"},{"key":"2025100315024287000_8.1.e000842.21","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1007\/s10147-017-1166-2","article-title":"Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors","volume":"22","author":"Yasuda","year":"2017","journal-title":"Int J Clin Oncol"},{"key":"2025100315024287000_8.1.e000842.22","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-03153-6","article-title":"Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients","volume":"7","author":"Hang","year":"2017","journal-title":"Sci Rep"},{"key":"2025100315024287000_8.1.e000842.23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ejca.2017.03.020","article-title":"Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer","volume":"79","author":"Pastorino","year":"2017","journal-title":"Eur J Cancer"},{"key":"2025100315024287000_8.1.e000842.24","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.suronc.2018.01.002","article-title":"Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: a comprehensive analysis of systemic inflammatory markers","volume":"27","author":"Akamine","year":"2018","journal-title":"Surg Oncol"},{"key":"2025100315024287000_8.1.e000842.25","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0412"},{"key":"2025100315024287000_8.1.e000842.26","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju124"},{"key":"2025100315024287000_8.1.e000842.27","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0383-1"},{"key":"2025100315024287000_8.1.e000842.28","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.180"},{"key":"2025100315024287000_8.1.e000842.29","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/cam4.1356","article-title":"Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma","volume":"7","author":"Rosner","year":"2018","journal-title":"Cancer Med"},{"key":"2025100315024287000_8.1.e000842.30","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30126-7"},{"key":"2025100315024287000_8.1.e000842.31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1001\/jamaoncol.2018.4514","article-title":"Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial","volume":"5","author":"Ascierto","year":"2019","journal-title":"JAMA Oncol"},{"key":"2025100315024287000_8.1.e000842.32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2025100315024287000_8.1.e000842.33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"2025100315024287000_8.1.e000842.34","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(18)30700-9"},{"key":"2025100315024287000_8.1.e000842.35","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000234"},{"key":"2025100315024287000_8.1.e000842.36","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0097"},{"key":"2025100315024287000_8.1.e000842.37","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2019.1593810","article-title":"Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer","volume":"8","author":"Hardy-Werbin","year":"2019","journal-title":"Oncoimmunology"},{"key":"2025100315024287000_8.1.e000842.38","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2015.1100788","article-title":"Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with ipilimumab","volume":"5","author":"Bjoern","year":"2016","journal-title":"Oncoimmunology"},{"key":"2025100315024287000_8.1.e000842.39","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0481-0"},{"key":"2025100315024287000_8.1.e000842.40","doi-asserted-by":"crossref","first-page":"e26642","DOI":"10.1002\/pbc.26642","article-title":"Severe cytokine release syndrome in a patient receiving PD-1-directed therapy","volume":"64","author":"Rotz","year":"2017","journal-title":"Pediatr Blood Cancer"},{"key":"2025100315024287000_8.1.e000842.41","doi-asserted-by":"crossref","first-page":"5294","DOI":"10.4049\/jimmunol.160.11.5294","article-title":"Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice","volume":"160","author":"Szalai","year":"1998","journal-title":"J Immunol"},{"key":"2025100315024287000_8.1.e000842.42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800717"},{"key":"2025100315024287000_8.1.e000842.43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.3.461"},{"key":"2025100315024287000_8.1.e000842.44","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00078-9"},{"key":"2025100315024287000_8.1.e000842.45","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1610"},{"key":"2025100315024287000_8.1.e000842.46","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/cas.13433","article-title":"Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity","volume":"109","author":"Tsukamoto","year":"2018","journal-title":"Cancer Sci"},{"key":"2025100315024287000_8.1.e000842.47","doi-asserted-by":"crossref","DOI":"10.1186\/s12865-018-0241-4","article-title":"Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer","volume":"19","author":"Jackute","year":"2018","journal-title":"BMC Immunol"},{"key":"2025100315024287000_8.1.e000842.48","first-page":"581","article-title":"Tumorinfiltrating M2 macrophages driven by specific genomic alterations are associated with prognosis in bladder cancer","volume":"42","author":"Xue","year":"2019","journal-title":"Oncol Rep"},{"key":"2025100315024287000_8.1.e000842.49","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016295"},{"key":"2025100315024287000_8.1.e000842.50","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-311585"},{"key":"2025100315024287000_8.1.e000842.51","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/ijc.31331","article-title":"Immune checkpoint blockade combined with IL-6 and TGF-\u03b2 inhibition improves the therapeutic outcome of mRNA-based immunotherapy","volume":"143","author":"Bialkowski","year":"2018","journal-title":"Int J Cancer"},{"key":"2025100315024287000_8.1.e000842.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.02.128"},{"key":"2025100315024287000_8.1.e000842.53","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/djv199","article-title":"Circulating inflammation markers, risk of lung cancer, and utility for risk stratification","volume":"107","author":"Shiels","year":"2015","journal-title":"J Natl Cancer Inst"},{"key":"2025100315024287000_8.1.e000842.54","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.0554"},{"key":"2025100315024287000_8.1.e000842.55","doi-asserted-by":"publisher","DOI":"10.1007\/s12307-010-0052-5"},{"key":"2025100315024287000_8.1.e000842.56","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2734"},{"key":"2025100315024287000_8.1.e000842.57","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-03-564450"},{"key":"2025100315024287000_8.1.e000842.58","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0736"},{"key":"2025100315024287000_8.1.e000842.59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002067"},{"key":"2025100315024287000_8.1.e000842.60","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1293"},{"key":"2025100315024287000_8.1.e000842.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.10.010"},{"key":"2025100315024287000_8.1.e000842.62","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402909"},{"key":"2025100315024287000_8.1.e000842.63","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00372","article-title":"C-Reactive protein impairs dendritic cell development, maturation, and function: implications for peripheral tolerance","volume":"9","author":"Jimenez","year":"2018","journal-title":"Front Immunol"},{"key":"2025100315024287000_8.1.e000842.64","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2019.37.15_suppl.100","article-title":"Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition","volume":"37","author":"Weber","year":"2019","journal-title":"J Clin Oncol"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-000842","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T22:02:50Z","timestamp":1759528970000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-000842"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,6,23]]},"published-print":{"date-parts":[[2020,6]]}},"alternative-id":["10.1136\/jitc-2020-000842"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-000842","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6]]}}}