{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:19:15Z","timestamp":1793744355559,"version":"4.6.1"},"reference-count":66,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"unspecified","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Providence Portland Medical Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100022781","name":"Galectin Therapeutics","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100022781","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/NCI","award":["R21CA190790"],"award-info":[{"award-number":["R21CA190790"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,3,8]]},"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>PD-1\/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02575404\">NCT02575404<\/jats:ext-link>). Belapectin was administered at 2, 4, or 8\u2009mg\/kg IV 60\u2009min before pembrolizumab (200\u2009mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0\u20132, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Objective response was observed in 50% of MM (7\/14) and and 33% of HNSCC (2\/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002371","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T12:45:06Z","timestamp":1617972306000},"page":"e002371","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":102,"title":["Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02575404","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01899859","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02462967","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04365868","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02575404","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02575404","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02575404","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-2708","authenticated-orcid":false,"given":"Brendan D","family":"Curti","sequence":"first","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Koguchi","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-7938","authenticated-orcid":false,"given":"Rom S","family":"Leidner","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annah S","family":"Rolig","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R","family":"Sturgill","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Wu","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesh","family":"Rajamanickam","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brady","family":"Bernard","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Hilgart-Martiszus","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B","family":"Fountain","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Morris","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Shimadzu Bioscience Research Partnership, Shimadzu Scientific Instruments, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shimada","sequence":"additional","affiliation":[{"name":"Shimadzu Bioscience Research Partnership, Shimadzu Scientific Instruments, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ShuChing","family":"Chang","sequence":"additional","affiliation":[{"name":"Medical Data Research Center, Providence St Joseph Health, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G","family":"Traber","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliezer","family":"Zomer","sequence":"additional","affiliation":[{"name":"Galectin Therapeutics, Norcross, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Rex","family":"Horton","sequence":"additional","affiliation":[{"name":"Galectin Therapeutics, Norcross, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold","family":"Shlevin","sequence":"additional","affiliation":[{"name":"Galectin Therapeutics, Norcross, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2572-1731","authenticated-orcid":false,"given":"William L","family":"Redmond","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"2025100312141664000_9.4.e002371.1","doi-asserted-by":"publisher","DOI":"10.1038\/ni0702-611"},{"key":"2025100312141664000_9.4.e002371.2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1030"},{"key":"2025100312141664000_9.4.e002371.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"2025100312141664000_9.4.e002371.4","first-page":"viii15-21","article-title":"How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma","volume":"23 Suppl 8","author":"Wolchok","year":"2012","journal-title":"Ann Oncol"},{"key":"2025100312141664000_9.4.e002371.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60958-2"},{"key":"2025100312141664000_9.4.e002371.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1305133"},{"key":"2025100312141664000_9.4.e002371.7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4100"},{"key":"2025100312141664000_9.4.e002371.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203479109"},{"key":"2025100312141664000_9.4.e002371.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0915174107"},{"key":"2025100312141664000_9.4.e002371.10","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0022"},{"key":"2025100312141664000_9.4.e002371.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"2025100312141664000_9.4.e002371.12","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nrd.2018.167","article-title":"Trends in the global immuno-oncology landscape","volume":"17","author":"Tang","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"2025100312141664000_9.4.e002371.13","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399408000719"},{"key":"2025100312141664000_9.4.e002371.14","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2012.44.6.044"},{"key":"2025100312141664000_9.4.e002371.15","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2012-5757"},{"key":"2025100312141664000_9.4.e002371.16","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080380"},{"key":"2025100312141664000_9.4.e002371.17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2650"},{"key":"2025100312141664000_9.4.e002371.18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00798.x"},{"key":"2025100312141664000_9.4.e002371.19","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1434467","article-title":"The role of galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment","volume":"7","author":"Farhad","year":"2018","journal-title":"Oncoimmunology"},{"key":"2025100312141664000_9.4.e002371.20","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20071607","article-title":"Predictive biomarkers for checkpoint inhibitor-based immunotherapy: the galectin-3 signature in NSCLCs","volume":"20","author":"Capalbo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2025100312141664000_9.4.e002371.21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0761"},{"key":"2025100312141664000_9.4.e002371.22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-2244"},{"key":"2025100312141664000_9.4.e002371.23","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1053\/j.gastro.2019.11.296","article-title":"Effects of Belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension","volume":"158","author":"Chalasani","year":"2020","journal-title":"Gastroenterology"},{"key":"2025100312141664000_9.4.e002371.24","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.jaad.2017.05.055","article-title":"A phase 2A, open-label pilot study of the galectin-3 inhibitor GR-MD-02 for the treatment of moderate-to-severe plaque psoriasis","volume":"77","author":"Ritchie","year":"2017","journal-title":"J Am Acad Dermatol"},{"key":"2025100312141664000_9.4.e002371.25","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13816"},{"key":"2025100312141664000_9.4.e002371.26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.8.4622"},{"key":"2025100312141664000_9.4.e002371.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083481"},{"key":"2025100312141664000_9.4.e002371.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2011.11.014"},{"key":"2025100312141664000_9.4.e002371.29","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12150"},{"key":"2025100312141664000_9.4.e002371.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.01.004"},{"key":"2025100312141664000_9.4.e002371.31","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80005"},{"key":"2025100312141664000_9.4.e002371.32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701019"},{"key":"2025100312141664000_9.4.e002371.33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2027"},{"key":"2025100312141664000_9.4.e002371.34","doi-asserted-by":"crossref","DOI":"10.1001\/jamaoncol.2019.1549","article-title":"Comparison of biomarker modalities for predicting response to PD-1\/PD-L1 checkpoint blockade: a systematic review and meta-analysis","author":"Lu","year":"2019","journal-title":"JAMA Oncol"},{"key":"2025100312141664000_9.4.e002371.35","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2019-206252"},{"key":"2025100312141664000_9.4.e002371.36","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-3167"},{"key":"2025100312141664000_9.4.e002371.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0357-y"},{"key":"2025100312141664000_9.4.e002371.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0734-6"},{"key":"2025100312141664000_9.4.e002371.39","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41586-020-2056-8","article-title":"Peripheral T cell expansion predicts tumour infiltration and clinical response","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"2025100312141664000_9.4.e002371.40","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0415"},{"key":"2025100312141664000_9.4.e002371.41","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejca.2018.12.008","article-title":"Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer","volume":"109","author":"Basak","year":"2019","journal-title":"Eur J Cancer"},{"key":"2025100312141664000_9.4.e002371.42","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00083-2"},{"key":"2025100312141664000_9.4.e002371.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31601-X"},{"key":"2025100312141664000_9.4.e002371.44","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30066-3"},{"key":"2025100312141664000_9.4.e002371.45","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602252"},{"key":"2025100312141664000_9.4.e002371.46","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32591-7"},{"key":"2025100312141664000_9.4.e002371.47","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31999-8"},{"key":"2025100312141664000_9.4.e002371.48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1503093"},{"key":"2025100312141664000_9.4.e002371.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705327114"},{"key":"2025100312141664000_9.4.e002371.50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lungcan.2020.07.028","article-title":"Soluble PD-L1 and circulating CD8+PD-1+ and NK cells enclose a prognostic and predictive immune effector score in immunotherapy treated NSCLC patients","volume":"148","author":"Mazzaschi","year":"2020","journal-title":"Lung Cancer"},{"key":"2025100312141664000_9.4.e002371.51","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21072411","article-title":"Systemic blood immune cell populations as biomarkers for the outcome of immune checkpoint inhibitor therapies","volume":"21","author":"Hernandez","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2025100312141664000_9.4.e002371.52","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1508-5"},{"key":"2025100312141664000_9.4.e002371.53","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-018-1563-y","article-title":"Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma","volume":"16","author":"Retseck","year":"2018","journal-title":"J Transl Med"},{"key":"2025100312141664000_9.4.e002371.54","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0193"},{"key":"2025100312141664000_9.4.e002371.55","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0669-y"},{"key":"2025100312141664000_9.4.e002371.56","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1847"},{"key":"2025100312141664000_9.4.e002371.57","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0164"},{"key":"2025100312141664000_9.4.e002371.58","article-title":"A semi-automated approach to preparing antibody cocktails for immunophenotypic analysis of human peripheral blood","volume":"108","author":"Koguchi","year":"2016","journal-title":"J Vis Exp"},{"key":"2025100312141664000_9.4.e002371.59","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1652"},{"key":"2025100312141664000_9.4.e002371.60","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.pharmthera.2017.12.007","article-title":"Recent advances in mass spectrometry-based approaches for proteomics and biologics: great contribution for developing therapeutic antibodies","volume":"185","author":"Iwamoto","year":"2018","journal-title":"Pharmacol Ther"},{"key":"2025100312141664000_9.4.e002371.61","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1039\/C3AN02104A","article-title":"Selective detection of complementarity-determining regions of monoclonal antibody by limiting protease access to the substrate: nano-surface and molecular-orientation limited proteolysis","volume":"139","author":"Iwamoto","year":"2014","journal-title":"Analyst"},{"key":"2025100312141664000_9.4.e002371.62","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCELL.2019.01.003"},{"key":"2025100312141664000_9.4.e002371.63","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"2025100312141664000_9.4.e002371.64","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-Seq: transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Res"},{"key":"2025100312141664000_9.4.e002371.65","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2025100312141664000_9.4.e002371.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2013.06.009"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-002371","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T19:14:26Z","timestamp":1759518866000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-002371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":66,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,9]]},"published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1136\/jitc-2021-002371"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-002371","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4]]}}}