{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T07:27:48Z","timestamp":1789198068785,"version":"build-2803163510"},"reference-count":156,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells\u2019 responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.<\/jats:p>","DOI":"10.3390\/ijms21124427","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T06:11:02Z","timestamp":1592892662000},"page":"4427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":124,"title":["Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0398-6587","authenticated-orcid":false,"given":"Omid","family":"Kooshkaki","sequence":"first","affiliation":[{"name":"Student research committee, Birjand University of Medical Sciences, Birjand 9717853577, Iran"},{"name":"Department of Immunology, Birjand University of Medical Sciences, Birjand 9717853577, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3243-233X","authenticated-orcid":false,"given":"Afshin","family":"Derakhshani","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3870-4145","authenticated-orcid":false,"given":"Negar","family":"Hosseinkhani","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra","family":"Torabi","sequence":"additional","affiliation":[{"name":"Student research committee, Tabriz University of medical sciences, Tabriz 5165665811, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Safaei","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7014-6828","authenticated-orcid":false,"given":"Oronzo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, IRCCS IstitutoTumori \u201cGiovanni Paolo II\u201d of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8639-1940","authenticated-orcid":false,"given":"Vito","family":"Racanelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7814-7318","authenticated-orcid":false,"given":"Nicola","family":"Silvestris","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, IRCCS IstitutoTumori \u201cGiovanni Paolo II\u201d of Bari, 70124 Bari, Italy"},{"name":"Department of Biomedical Sciences and Human Oncology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8642-6795","authenticated-orcid":false,"given":"Behzad","family":"Baradaran","sequence":"additional","affiliation":[{"name":"Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran"},{"name":"Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.3390\/cancers3033279","article-title":"Assessment of the evolution of cancer treatment therapies","volume":"3","author":"Arruebo","year":"2011","journal-title":"Cancers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"232","DOI":"10.12688\/f1000research.6760.1","article-title":"Chemotherapy for Late-Stage Cancer Patients: Meta-Analysis of Complete Response Rates","volume":"4","author":"Ashdown","year":"2015","journal-title":"F1000Research"},{"key":"ref_3","first-page":"384","article-title":"Intestinal stem cell injury and protection during cancer therapy","volume":"2","author":"Yu","year":"2013","journal-title":"Transl. 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