{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:48:50Z","timestamp":1774356530670,"version":"3.50.1"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T00:00:00Z","timestamp":1393804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific \u201cimmune-related adverse events\u201d (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique \u201cinnocent bystander\u201d effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment.<\/jats:p>","DOI":"10.3390\/toxins6030914","type":"journal-article","created":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T11:27:10Z","timestamp":1393846030000},"page":"914-933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an \u201cInnocent Bystander\u201d"],"prefix":"10.3390","volume":"6","author":[{"given":"Lucia","family":"Gelao","sequence":"first","affiliation":[{"name":"Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Criscitiello","sequence":"additional","affiliation":[{"name":"Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aron","family":"Goldhirsch","sequence":"additional","affiliation":[{"name":"Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Curigliano","sequence":"additional","affiliation":[{"name":"Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(06)90001-7","article-title":"Cancer immunosurveillance and immunoediting: The roles of immunity in suppressing tumor development and shaping tumor immunogenicity","volume":"90","author":"Smyth","year":"2006","journal-title":"Adv. Immunol."},{"key":"ref_2","first-page":"369","article-title":"The immune system and cancer","volume":"24","author":"Loose","year":"2009","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e25961","DOI":"10.4161\/onci.25961","article-title":"Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy","volume":"2","author":"Devaud","year":"2013","journal-title":"Oncoimmunology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s12307-012-0122-y","article-title":"Tumor-infiltrating regulatory T cells: Phenotype, role, mechanism of expansion in situ and clinical significance","volume":"6","author":"Tanchot","year":"2013","journal-title":"Cancer Microenviron."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5373","DOI":"10.1200\/JCO.2006.05.9584","article-title":"Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse","volume":"24","author":"Bates","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18538","DOI":"10.1073\/pnas.0509182102","article-title":"Intraepithelial CD8+ tumor infiltrating lymphocytes and a high CD8+\/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer","volume":"102","author":"Sato","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1158\/1078-0432.CCR-05-1886","article-title":"Prognostic value of tumor infiltrating CD4+ T-cell subpopulations in head and neck cancers","volume":"12","author":"Badoual","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1002\/ijc.24989","article-title":"High frequency of tumor-infiltrating FOXP3 (+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients","volume":"126","author":"Frey","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","article-title":"Ipilimumab plus dacarbazine for previously untreated metastatic melanoma","volume":"364","author":"Robert","year":"2011","journal-title":"New Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"New Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti-PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"New Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1007\/s12185-011-0799-6","article-title":"The mechanisms of cancer immunoescape and development of overcoming strategies","volume":"93","author":"Yaguchi","year":"2011","journal-title":"Int. J. Hematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s12026-007-0073-4","article-title":"Monoclonal antibody mechanisms of action in cancer","volume":"39","author":"Weiner","year":"2007","journal-title":"Immunol. Res."},{"key":"ref_14","first-page":"10","article-title":"New directions in cellular therapy of cancer: A summary of the summit on cellular therapy for cancer","volume":"15","author":"Stroncek","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.molonc.2012.01.002","article-title":"Cancer immunotherapy","volume":"6","author":"Gajewski","year":"2012","journal-title":"Mol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0065-2776(06)90008-X","article-title":"Checkpoint blockade in cancer immunotherapy","volume":"90","author":"Korman","year":"2006","journal-title":"Adv. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1517\/14712598.2010.529126","article-title":"T regulatory cells in cancer: Recent advances and therapeutic potential","volume":"10","author":"Elkord","year":"2010","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.2217\/imt.12.116","article-title":"Depletion of Tregs in vivo: A promising approach to enhance antitumor immunity without autoimmunity","volume":"4","author":"Morita","year":"2012","journal-title":"Immunotherapy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00262-010-0967-1","article-title":"Suppression of Tcell responses by tumor metabolites","volume":"60","author":"Singer","year":"2011","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_20","first-page":"41","article-title":"STAT3: A target to enhance antitumor immune response","volume":"344","author":"Lee","year":"2011","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1189\/jlb.1212631","article-title":"At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy","volume":"94","author":"Callahan","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3322\/caac.20132","article-title":"Immunotherapy of cancer in 2012","volume":"62","author":"Kirkwood","year":"2012","journal-title":"CA Cancer J. Clin."},{"key":"ref_23","first-page":"579","article-title":"Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies","volume":"10","author":"Khubchandani","year":"2009","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nri823","article-title":"Activation rules: The two-signal theories of immune activation","volume":"2","author":"Baxter","year":"2000","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1084\/jem.20082492","article-title":"Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies","volume":"206","author":"Peggs","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1074-7613(00)80480-X","article-title":"Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement","volume":"4","author":"Linsley","year":"1996","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1074-7613(00)80366-0","article-title":"The emerging role of CTLA-4 as an immune attenuator","volume":"7","author":"Thompson","year":"1997","journal-title":"Immunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2174\/138161206775193046","article-title":"Mechanisms of CTLA-4-Ig in tolerance induction","volume":"12","author":"Alegre","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.192.2.303","article-title":"Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4","volume":"192","author":"Takahashi","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1146\/annurev-med-092012-112807","article-title":"Immune Modulation in Cancer with Antibodies","volume":"65","author":"Page","year":"2014","journal-title":"Annu. Rev. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.febslet.2013.10.015","article-title":"Checkpoint blocking antibodies in cancer immunotherapy","volume":"588","author":"Kyi","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1126\/science.291.5502.319","article-title":"Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice","volume":"5502","author":"Nishimura","year":"2001","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S1074-7613(00)80089-8","article-title":"Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor","volume":"11","author":"Nishimura","year":"1999","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nri1570","article-title":"MHC class I molecules and KIRs in human history, health and survival","volume":"5","author":"Parham","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"Abstract 3007","DOI":"10.1200\/jco.2008.26.15_suppl.3007","article-title":"Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA)","volume":"26","author":"Sznol","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1053\/j.seminoncol.2010.09.002","article-title":"Biology and clinical applications of CD40 in cancer treatment","volume":"37","author":"Fonsatti","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.4049\/jimmunol.161.7.3347","article-title":"Expression and function of CTLA-4 in Th1 and Th2 cells","volume":"161","author":"Alegre","year":"1998","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1093\/annonc\/mdt107","article-title":"Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: Results from an open-label, multicenter phase I\/II study","volume":"24","author":"Slovin","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1517\/14712598.2012.681371","article-title":"Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer","volume":"12","author":"Genova","year":"2012","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/CJI.0b013e3181eec14c","article-title":"Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma","volume":"33","author":"Royal","year":"2010","journal-title":"J. Immunother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1097\/CJI.0b013e318156e47e","article-title":"Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis","volume":"30","author":"Yang","year":"2007","journal-title":"J. Immunother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"New Engl. J. Med."},{"key":"ref_43","unstructured":"ClinicalTrials.gov. Available online:http:\/\/www.clinicaltrials.gov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1053\/j.seminoncol.2010.09.010","article-title":"Clinical development of the anti-CTLA-4 antibody tremelimumab","volume":"37","author":"Ribas","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1200\/JCO.2008.19.2435","article-title":"Phase I\/II trial of tremelimumab in patients with metastatic melanoma","volume":"27","author":"Camacho","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1200\/JCO.2012.44.6112","article-title":"Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma","volume":"31","author":"Ribas","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1158\/1078-0432.CCR-09-2870","article-title":"Modulation of lymphocyte regulation for cancer therapy: A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma","volume":"16","author":"Ralph","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8071","DOI":"10.1200\/jco.2009.27.15_suppl.8071","article-title":"Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following firstline platinum-based therapy in patients with advanced non-small cell lung cancer (NSCLC)","volume":"27","author":"Zatloukal","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1200\/JCO.2010.28.3994","article-title":"Phase II study of the anti-cytotoxic T-lymphocyte associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer","volume":"28","author":"Chung","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sznol, M., Kluger, H.M., Hodi, F.S., McDermott, D.F., Carvajal, R.D., Lawrence, D.P., Topalian, S.L., Atkins, M.B., Powderly, J.D., and Sharfman, W.H. (2013). Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J. Clin. Oncol., 31, 2013: CRA9006.","DOI":"10.1200\/jco.2013.31.18_suppl.cra9006"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab plus Ipilimumab in advanced melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"New Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1056\/NEJMoa1305133","article-title":"Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma","volume":"369","author":"Hamid","year":"2013","journal-title":"New Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1182\/blood-2010-01-265975","article-title":"B7-H1\/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance","volume":"116","author":"Park","year":"2010","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Herbst, R.S., Gordon, M.S., Fine, G.D., Sosman, J.A., Soria, J.-C., Hamid, O., Powderly, J.D., Burris, H.A., Mokatrin, A., and Kowanetz, M. (2013\u20134, January 31). A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. Proceedings of the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.","DOI":"10.1200\/jco.2013.31.15_suppl.3000"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Tabernero, J., Powderly, J.D., Hamid, O., Gordon, M.S., Fisher, G.A., Braiteh, F.S., Garbo, L.E., Fine, G.D., Kowanetz, M., and McCall, B. (June, January 31). Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors. Proceedings of the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.","DOI":"10.1200\/jco.2013.31.15_suppl.3622"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/nm934","article-title":"Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase","volume":"9","author":"Uyttenhove","year":"2003","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1479-5876-6-12","article-title":"Transient T cell depletion causes regression of melanoma metastases","volume":"6","author":"Rasku","year":"2008","journal-title":"J. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1749-6632.2009.04939.x","article-title":"Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells","volume":"1174","author":"Rech","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_59","unstructured":"Phase II, 2nd Line Melanoma: RAND Monotherapy. Available online:http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00612664."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7189","DOI":"10.1158\/0008-5472.CAN-12-4174","article-title":"OX40 is a potent immune-stimulating target in late-stage cancer patients","volume":"73","author":"Curti","year":"2013","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1053\/j.seminoncol.2010.09.003","article-title":"Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: Identification of clinical and biological response patterns, immune-related adverse events, and their management","volume":"37","author":"Kaehler","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","article-title":"Enhancement of antitumor immunity by CTLA-4 blockade","volume":"271","author":"Leach","year":"1996","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1084\/jem.190.3.355","article-title":"Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte\/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation","volume":"190","author":"Hurwitz","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/1074-7613(95)90125-6","article-title":"Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4","volume":"3","author":"Borriello","year":"1995","journal-title":"Immunity"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1126\/science.270.5238.985","article-title":"Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4","volume":"270","author":"Waterhouse","year":"1995","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0165-5728(96)00168-3","article-title":"Specific blockade of CTLA-4\/B7 interactions results in exacerbated clinical and histologic disease in an actively induced model of experimental allergic encephalomyelitis","volume":"73","author":"Hurwitz","year":"1997","journal-title":"J. Neuroimmunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.4049\/jimmunol.157.4.1333","article-title":"CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis","volume":"157","author":"Perrin","year":"1996","journal-title":"J. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1084\/jem.187.3.427","article-title":"Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes","volume":"187","author":"Luhder","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_69","first-page":"2444","article-title":"Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade","volume":"60","author":"Hurwitz","year":"2000","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8372","DOI":"10.1073\/pnas.1533209100","article-title":"Cancer regression and autoimmunity induced by cytotoxic lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma","volume":"100","author":"Phan","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1245\/ASO.2005.03.536","article-title":"Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I\/II study","volume":"12","author":"Maker","year":"2005","journal-title":"Ann. Surg. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1200\/JCO.2012.41.6750","article-title":"Management of immune related adverse events and kinetics of response with ipilimumab","volume":"30","author":"Weber","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3747\/co.20.1265","article-title":"Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: Two illustrative cases","volume":"20","author":"Assi","year":"2013","journal-title":"Curr. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1200\/JCO.2005.04.5716","article-title":"Enterocolitis in patients after antibody blockade of CTLA-4","volume":"24","author":"Beck","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1053\/j.seminoncol.2010.09.015","article-title":"Development of ipilimumab: Contribution to a new paradigm for cancer immunotherapy","volume":"37","author":"Hoos","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5275","DOI":"10.1200\/JCO.2008.17.8954","article-title":"Anti-cytotoxic T-lymphocyte antigen-4 antibody: The first in an emerging class of immunomodulatory antibodies for cancer treatment","volume":"26","author":"Fong","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1634\/theoncologist.2012-0483","article-title":"Ipilimumab and its toxicities: A multidisciplinary approach","volume":"18","author":"Hodi","year":"2013","journal-title":"Oncologist"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1016\/j.ejca.2013.07.001","article-title":"Drug of the year: Programmed death-1 receptor\/programmed death-1 ligand-1 receptor monoclonal antibodies","volume":"49","author":"Robert","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4194","DOI":"10.4049\/jimmunol.178.7.4194","article-title":"Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice","volume":"178","author":"Niu","year":"2007","journal-title":"J. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1053\/j.seminoncol.2010.09.008","article-title":"Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies","volume":"37","author":"Ascierto","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"845","DOI":"10.3324\/haematol.2009.008003","article-title":"A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma","volume":"95","author":"Hussein","year":"2010","journal-title":"Haematologica"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3109\/10428190903440946","article-title":"A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia","volume":"51","author":"Furman","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1200\/JCO.2008.21.3017","article-title":"Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin\u2019s lymphoma","volume":"27","author":"Advani","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1126\/scitranslmed.3003330","article-title":"CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients","volume":"4","author":"Rech","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.1158\/1078-0432.CCR-07-0187","article-title":"Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade","volume":"13","author":"Downey","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/CMR.0b013e32835fb524","article-title":"Ipilimumab-induced acute severe colitis treated by infliximab","volume":"23","author":"Pages","year":"2013","journal-title":"Melanoma Res."},{"key":"ref_87","unstructured":"Bristol-MyersSquibb Risk evaluation and mitigation strategy for Yervoy (Ipilimumab) on the risks of and recommended management for severe immune-mediated adverse reaction. Available online:http:\/\/www.fda.gov\/downloads\/Drugs\/DrugSafety\/PostmarketDrugSafetyInformationforPatientsandProviders\/UCM249435.pdf."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Lutzky, J., Wolchok, J., Hamid, O., Lebbe, L., Pehamberger, H., Linette, G., de Pril, V., Ibrahim, R., Hoos, A., and O'Day, S. (2009). Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg\/kg ipilimumab in three phase II clinical trials. J. Clin. Oncol., 27, 2009: 9034.","DOI":"10.1200\/jco.2009.27.15_suppl.9034"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1158\/1078-0432.CCR-09-1024","article-title":"A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma","volume":"15","author":"Weber","year":"2009","journal-title":"Clin. Cancer Res."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/6\/3\/914\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:08:47Z","timestamp":1760216927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/6\/3\/914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,3]]},"references-count":89,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,3]]}},"alternative-id":["toxins6030914"],"URL":"https:\/\/doi.org\/10.3390\/toxins6030914","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,3]]}}}