{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:45:47Z","timestamp":1782935147813,"version":"3.54.5"},"reference-count":43,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"641","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,4,20]]},"abstract":"<jats:p>The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti\u2013programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti\u2013PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-na\u00efve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti\u2013PD-1 therapy in advanced ccRCC.<\/jats:p>","DOI":"10.1126\/scitranslmed.abm6420","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T17:52:41Z","timestamp":1650477161000},"source":"Crossref","is-referenced-by-count":59,"title":["A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6505-8308","authenticated-orcid":true,"given":"Pavlos","family":"Msaouel","sequence":"first","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-4503","authenticated-orcid":true,"given":"Sangeeta","family":"Goswami","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter F.","family":"Thall","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3516-0966","authenticated-orcid":true,"given":"Xuemei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0943-2806","authenticated-orcid":true,"given":"Eric","family":"Jonasch","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-4472","authenticated-orcid":true,"given":"Jianjun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-4491","authenticated-orcid":true,"given":"Matthew T.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-0621","authenticated-orcid":true,"given":"Amishi Yogesh","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4106-6335","authenticated-orcid":true,"given":"Paul Gettys","family":"Corn","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-1556","authenticated-orcid":true,"given":"Alda L.","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-2300","authenticated-orcid":true,"given":"Kamran","family":"Ahrar","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5672-0961","authenticated-orcid":true,"given":"Priya","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-697X","authenticated-orcid":true,"given":"Kanishka","family":"Sircar","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Palliative, Rehabilitation and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5028-3833","authenticated-orcid":true,"given":"Sreyashi","family":"Basu","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Duan","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3911-6815","authenticated-orcid":true,"given":"Sonali","family":"Jindal","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2315-0645","authenticated-orcid":true,"given":"Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-5548","authenticated-orcid":true,"given":"Shalini S.","family":"Yadav","sequence":"additional","affiliation":[{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-3436","authenticated-orcid":true,"given":"Ronald","family":"Shazer","sequence":"additional","affiliation":[{"name":"Mirati Therapeutics Inc., San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-5712","authenticated-orcid":true,"given":"Hirak","family":"Der-Torossian","sequence":"additional","affiliation":[{"name":"Mirati Therapeutics Inc., San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-5697","authenticated-orcid":true,"given":"James P.","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-055X","authenticated-orcid":true,"given":"Padmanee","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-8060","authenticated-orcid":true,"given":"Nizar M.","family":"Tannir","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2020.100166"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.015"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.013"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.03.007"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6547"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124184"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx795"},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","unstructured":"Y. Yuan H. Q. Nguyen P. F. Thall Bayesian designs for phase I-II clinical trials (Chapman & Hall\/CRC Biostatistics series CRC Press Taylor & Francis Group 2016) pp. xiv.","DOI":"10.1201\/b21600"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.2014.881740"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-6073-7"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8020203"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK_201215"},{"key":"e_1_3_3_15_2","doi-asserted-by":"crossref","first-page":"e0211105","DOI":"10.1371\/journal.pone.0211105","article-title":"Liver metastasis and Heng risk are prognostic factors in patients with non-nephrectomized synchronous metastatic renal cell carcinoma treated with systemic therapy","volume":"14","author":"Kim S. H.","year":"2019","unstructured":"S. H. Kim, J. K. Kim, E. Y. Park, J. Joo, K. H. Lee, H. K. Seo, J. Y. Joung, J. Chung, Liver metastasis and Heng risk are prognostic factors in patients with non-nephrectomized synchronous metastatic renal cell carcinoma treated with systemic therapy. PLoS One 14, e0211105 (2019).","journal-title":"PLoS One"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1131-x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01190-9"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0425-8"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.746976"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510016"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33033"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510665"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712126"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1816714"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01652"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02627"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1816047"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035716"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2026982"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4308"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.04.016"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1033"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0220101"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.acra.2020.06.014"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1037\/0882-7974.12.2.277"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.3.570"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1037\/0278-6133.20.1.20"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.11622.1"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.10.029"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1177\/1740774514547397"},{"key":"e_1_3_3_42_2","doi-asserted-by":"crossref","unstructured":"A. Gelman J. B. Carlin H. S. Stern D. B. Dunson A. Vehtari D. B. Rubin Bayesian Data Analysis (Taylor & Francis ed. 3 2013).","DOI":"10.1201\/b16018"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70559-4"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/1467-9868.00353"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abm6420","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T17:20:03Z","timestamp":1705425603000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abm6420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,20]]},"references-count":43,"journal-issue":{"issue":"641","published-print":{"date-parts":[[2022,4,20]]}},"alternative-id":["10.1126\/scitranslmed.abm6420"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abm6420","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,20]]},"article-number":"eabm6420"}}