{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T12:10:16Z","timestamp":1784635816943,"version":"3.55.0"},"reference-count":47,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["clinical-genitourinary-cancer.com","clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genitourinary Cancer"],"published-print":{"date-parts":[[2022,6]]},"DOI":"10.1016\/j.clgc.2022.01.010","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T21:01:19Z","timestamp":1644354079000},"page":"252-259","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":12,"title":["Coordinated Pembrolizumab and High Dose IL-2 (5-in-a-Row Schedule) for Therapy of Metastatic Clear Cell Renal Cancer"],"prefix":"10.1016","volume":"20","author":[{"given":"Jonathan","family":"Chatzkel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Schell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jad","family":"Chahoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-3191","authenticated-orcid":false,"given":"Jennifer","family":"Swank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Ludlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Lombardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesenia","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cortlin","family":"Croft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Rembisz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gigi","family":"Jameel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayer","family":"Fishman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.clgc.2022.01.010_bib0001","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.immuni.2010.08.004","article-title":"Interleukin-2 receptor signaling: at the interface between tolerance and immunity","volume":"33","author":"Malek","year":"2010","journal-title":"Immunity"},{"key":"10.1016\/j.clgc.2022.01.010_bib0002","first-page":"S55","article-title":"Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma","volume":"6","author":"Fisher","year":"2000","journal-title":"Cancer J Sci Am"},{"key":"10.1016\/j.clgc.2022.01.010_bib0003","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.3390\/cancers3043856","article-title":"Cytokines in cancer immunotherapy","volume":"3","author":"Lee","year":"2011","journal-title":"Cancers"},{"key":"10.1016\/j.clgc.2022.01.010_bib0004","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s00262-016-1910-x","article-title":"Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma","volume":"65","author":"Alva","year":"2016","journal-title":"Cancer Immunol Immunother"},{"key":"10.1016\/j.clgc.2022.01.010_bib0005","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1200\/JCO.2005.03.206","article-title":"Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma","volume":"23","author":"McDermott","year":"2022","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0006","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1158\/1078-0432.CCR-14-1520","article-title":"The high-dose aldesleukin \"select\" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma","volume":"21","author":"McDermott","year":"2015","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.clgc.2022.01.010_bib0007","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/S1470-2045(19)30413-9","article-title":"Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial","volume":"20","author":"Motzer","year":"2019","journal-title":"Lancet Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0008","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/PPO.0000000000000059","article-title":"Biochemical signaling of PD-1 on T cells and its functional implications","volume":"20","author":"Boussiotis","year":"2014","journal-title":"Cancer J (Sudbury, Mass.)"},{"key":"10.1016\/j.clgc.2022.01.010_bib0009","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00262-017-1954-6","article-title":"PD-1 and PD-L1 antibodies in cancer: current status and future directions","volume":"66","author":"Balar","year":"2017","journal-title":"Cancer Immunol Immunother"},{"key":"10.1016\/j.clgc.2022.01.010_bib0010","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3389\/fphar.2017.00561","article-title":"PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome","volume":"8","author":"Alsaab","year":"2017","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0011","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus everolimus in advanced renal-cell carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N Engl J Med"},{"key":"10.1016\/j.clgc.2022.01.010_bib0012","series-title":"Pembrolizumab Monotherapy as First-Line Therapy In Advanced Clear Cell Renal Cell Carcinoma (accRCC): Results From Cohort A of KEYNOTE-427","author":"McDermott","year":"2018"},{"key":"10.1016\/j.clgc.2022.01.010_bib0013","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0014","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1056\/NEJMoa1816047","article-title":"Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma","volume":"380","author":"Motzer","year":"2019","journal-title":"N Engl J Med"},{"key":"10.1016\/j.clgc.2022.01.010_bib0015","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1056\/NEJMoa1816714","article-title":"Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma","volume":"380","author":"Rini","year":"2019","journal-title":"N Engl J Med"},{"key":"10.1016\/j.clgc.2022.01.010_bib0016","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1177\/1756287216663979","article-title":"Sunitinib in the treatment of metastatic renal cell carcinoma","volume":"8","author":"Schmid","year":"2016","journal-title":"Therap Adv Urol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0017","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1016\/j.cell.2015.11.026","article-title":"SnapShot: renal cell carcinoma","volume":"163","author":"Turajlic","year":"2015","journal-title":"Cell"},{"key":"10.1016\/j.clgc.2022.01.010_bib0018","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa2026982","article-title":"Nivolumab plus Cabozantinib versus sunitinib for advanced renal-cell carcinoma","volume":"384","author":"Choueiri","year":"2021","journal-title":"N Engl J Med"},{"key":"10.1016\/j.clgc.2022.01.010_bib0019","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1056\/NEJMoa2035716","article-title":"Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma","volume":"384","author":"Motzer","year":"2021","journal-title":"N Engl J Med"},{"issue":"26","key":"10.1016\/j.clgc.2022.01.010_bib0020","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1158\/1078-0432.CCR-19-3323","article-title":"Targeting PD-1 or PD-L1 in metastatic kidney cancer-combination therapy in the first line setting","volume":"1","author":"Aggen","year":"2020","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.clgc.2022.01.010_bib0021","unstructured":"Diab A, Hurwitz ME, Cho DC, et\u00a0al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1\/2 results of PIVOT.2022"},{"key":"10.1016\/j.clgc.2022.01.010_bib0022","unstructured":"Keytruda (pembrolizumab) injection label. Vol 2020."},{"key":"10.1016\/j.clgc.2022.01.010_bib0023","doi-asserted-by":"crossref","first-page":"255","DOI":"10.6004\/jnccn.2019.0013","article-title":"Management of immunotherapy-related toxicities, version 1.2019, NCCN clinical practice guidelines in oncology","volume":"17","author":"Thompson","year":"2019","journal-title":"J Natl Compr Cancer Netwk"},{"key":"10.1016\/j.clgc.2022.01.010_bib0024","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1093\/imammb\/dqw021","article-title":"The effects of interleukin-2 on immune response regulation","volume":"35","author":"Waters","year":"2018","journal-title":"Math Med Biol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0025","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9","article-title":"PD-1: PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2","volume":"32","author":"Carter","year":"2002","journal-title":"Eur J Immunol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0026","doi-asserted-by":"crossref","first-page":"6682","DOI":"10.4049\/jimmunol.0900080","article-title":"PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo","volume":"182","author":"Chikuma","year":"2009","journal-title":"J Immunol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0027","doi-asserted-by":"crossref","first-page":"5461","DOI":"10.1158\/1078-0432.CCR-15-2839","article-title":"Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma","volume":"22","author":"Choueiri","year":"2016","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.clgc.2022.01.010_bib0028","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40425-019-0522-3","article-title":"Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition","volume":"7","author":"Buchbinder","year":"2019","journal-title":"J Immunother Cancer"},{"key":"10.1016\/j.clgc.2022.01.010_bib0029","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/CJI.0000000000000024","article-title":"Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti-PD-1) treatment","volume":"37","author":"Brayer","year":"2014","journal-title":"J Immunother"},{"key":"10.1016\/j.clgc.2022.01.010_bib0030","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ejca.2016.03.081","article-title":"RECIST 1.1\u2014Update and clarification: From the RECIST committee","volume":"62","author":"Schwartz","year":"2016","journal-title":"Eur J Cancer"},{"key":"10.1016\/j.clgc.2022.01.010_bib0031","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/00000421-198212000-00014","article-title":"Toxicity and response criteria of the eastern cooperative oncology group","volume":"5","author":"Oken","year":"1982","journal-title":"Am J Clin Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0032","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1541-0420.2005.00311.x","article-title":"Continuous toxicity monitoring in phase II trials in oncology","volume":"61","author":"Ivanova","year":"2005","journal-title":"Biometrics"},{"key":"10.1016\/j.clgc.2022.01.010_bib0033","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1097\/CJI.0b013e3181ecccad","article-title":"Changes in dendritic cell phenotype after a new high-dose weekly schedule of interleukin-2 therapy for kidney cancer and melanoma","volume":"33","author":"Finkelstein","year":"2010","journal-title":"J Immunother"},{"key":"10.1016\/j.clgc.2022.01.010_bib0034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0197-2456(89)90015-9","article-title":"Optimal two-stage designs for phase II clinical trials","volume":"10","author":"Simon","year":"1989","journal-title":"Control Clin Trials"},{"key":"10.1016\/j.clgc.2022.01.010_bib0035","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/01621459.1927.10502953","article-title":"Probable inference, the law of succession, and statistical inference","volume":"22","author":"Wilson","year":"1927","journal-title":"J Am Stat Assoc"},{"key":"10.1016\/j.clgc.2022.01.010_bib0036","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40425-019-0567-3","article-title":"Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIM SM registry","volume":"7","author":"Fishman","year":"2019","journal-title":"J Immunother Cancer"},{"key":"10.1016\/j.clgc.2022.01.010_bib0037","first-page":"4202","article-title":"Recombinant interleukin 2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial","volume":"47","author":"Thompson","year":"1987","journal-title":"Cancer Res"},{"key":"10.1016\/j.clgc.2022.01.010_bib0038","first-page":"141","article-title":"Metabolic and renal effects of interleukin-2 immunotherapy for metastatic cancer","volume":"30","author":"Webb","year":"1988","journal-title":"Clin Nephrol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0039","first-page":"11","article-title":"Managing toxicities of high-dose interleukin-2","volume":"16","author":"Schwartz","year":"2002","journal-title":"Oncology (Williston Park, NY)"},{"key":"10.1016\/j.clgc.2022.01.010_bib0040","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1200\/JCO.19.00345","article-title":"Treatment-free survival: a novel outcome measure of the effects of immune checkpoint inhibition\u2014a pooled analysis of patients with advanced melanoma","volume":"37","author":"Regan","year":"2019","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0041","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1200\/JCO.18.02218","article-title":"Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study","volume":"37","author":"Flippot","year":"2019","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.clgc.2022.01.010_bib0042","unstructured":"Network NCC. NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2019 2019."},{"key":"10.1016\/j.clgc.2022.01.010_bib0043","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0147153","article-title":"Annual hospital volume of high dose interleukin-2 and inpatient mortality in melanoma and renal cell carcinoma patients","volume":"11","author":"Mehta","year":"2016","journal-title":"PloS One"},{"key":"10.1016\/j.clgc.2022.01.010_bib0044","article-title":"ARTISTRY-2: a phase 1\/2 study of subcutaneously administrated ALKS 4230 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors","volume":"7","author":"Powderly","year":"2019","journal-title":"J Immunother Cancer"},{"key":"10.1016\/j.clgc.2022.01.010_bib0045","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1158\/2159-8290.CD-18-1495","article-title":"A first-in-human study and biomarker analysis of NKTR-214, a novel IL2R\u03b2\u03b3-biased cytokine, in patients with advanced or metastatic solid tumors","volume":"9","author":"Bentebibel","year":"2019","journal-title":"Cancer Discov"},{"key":"10.1016\/j.clgc.2022.01.010_bib0046","series-title":"PDIGREE: An adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704)","author":"Zhang","year":"2019"},{"key":"10.1016\/j.clgc.2022.01.010_bib0047","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1158\/1078-0432.CCR-18-4070","article-title":"FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors","volume":"25","author":"Marcus","year":"2019","journal-title":"Clin Cancer Res"}],"container-title":["Clinical Genitourinary Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1558767322000234?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1558767322000234?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T11:35:26Z","timestamp":1761564926000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1558767322000234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["S1558767322000234"],"URL":"https:\/\/doi.org\/10.1016\/j.clgc.2022.01.010","relation":{},"ISSN":["1558-7673"],"issn-type":[{"value":"1558-7673","type":"print"}],"subject":[],"published":{"date-parts":[[2022,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Coordinated Pembrolizumab and High Dose IL-2 (5-in-a-Row Schedule) for Therapy of Metastatic Clear Cell Renal Cancer","name":"articletitle","label":"Article Title"},{"value":"Clinical Genitourinary Cancer","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.clgc.2022.01.010","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 The Authors. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}