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MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of approval for general application has not as yet been achieved. However, this does not appear to have quelled the interest in MUC1 as a therapeutic target, as shown by the increase in the number of MUC1-based clinical trials initiated in 2017 (Figure 1). As with all translational studies, incorporating new relevant research findings into therapeutic strategy is difficult. Decisions are made to commit to a specific strategy based on the information and data available when the trial is initiated. However, the time required for preclinical studies and early trials can render the founding concept not always appropriate for proceeding to a larger definitive trial. Here, we summarize the attempts made, to date, to bring MUC1 into the world of cancer immunotherapy and discuss how research findings regarding MUC1 structure and function together with expanded knowledge of its interactions with the tumour environment and immune effector cells could lead to improved therapeutic approaches.Figure 1.Number of MUC1-targeted trials initiated each year.\u003C\u002Fjats:p>",{"EN":107},"Latest developments in MUC1 immunotherapy",{"VOID":109},"29784646",{"VOID":111},"10.1042\u002Fbst20170400","PUBLICATION","VERIFIED","Auto 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1987, Cloning a cDNA coding for differentiation and tumour-associated mucin glycoprotein expressed by human mammary epithelium, Proc. Natl Acad. Sci. U.S.A., 84, 6060, 10.1073\u002Fpnas.84.17.6060",{"doi":241},"10.1073\u002Fpnas.84.17.6060",{"id":24,"text":243,"url":24,"identifiers":244},"Lan, 1990, Cloning and sequencing of a human pancreatic tumor mucin cDNA, J. Biol. Chem., 265, 15294, 10.1016\u002FS0021-9258(18)77255-4",{"doi":245},"10.1016\u002FS0021-9258(18)77255-4",{"id":24,"text":247,"url":24,"identifiers":248},"Ligtenberg, 1990, Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini, J. Biol. Chem., 265, 5573, 10.1016\u002FS0021-9258(19)39399-8",{"doi":249},"10.1016\u002FS0021-9258(19)39399-8",{"id":24,"text":251,"url":24,"identifiers":252},"Siddiqui, 1988, Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen, Proc. Natl Acad. Sci. U.S.A., 85, 2320, 10.1073\u002Fpnas.85.7.2320",{"doi":253},"10.1073\u002Fpnas.85.7.2320",{"id":24,"text":255,"url":24,"identifiers":256},"Baruch, 1999, The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein, Cancer Res., 59, 1552",{},{"id":24,"text":258,"url":24,"identifiers":259},"Julian,, 2009, MUC1 is a substrate for γ-secretase, J. Cell Biochem., 108, 802, 10.1002\u002Fjcb.22292",{"doi":260},"10.1002\u002Fjcb.22292",{"id":24,"text":262,"url":24,"identifiers":263},"Kufe,, 2013, MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches, Oncogene, 32, 1073, 10.1038\u002Fonc.2012.158",{"doi":264},"10.1038\u002Fonc.2012.158",{"id":24,"text":266,"url":24,"identifiers":267},"Kufe,, 2009, Mucins in cancer: function, prognosis and therapy, Nat. Rev. Cancer, 9, 874, 10.1038\u002Fnrc2761",{"doi":268},"10.1038\u002Fnrc2761",{"id":24,"text":270,"url":24,"identifiers":271},"Taylor-Papadimitriou, 1981, Monoclonal antibodies to epithelium-specific components of the human milk fat globule membrane: production and reaction with cells in culture, Int. J. Cancer, 28, 17, 10.1002\u002Fijc.2910280104",{"doi":272},"10.1002\u002Fijc.2910280104",{"id":24,"text":274,"url":24,"identifiers":275},"Hilkens,, 1984, Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumors, Int. J. Cancer, 34, 197, 10.1002\u002Fijc.2910340210",{"doi":276},"10.1002\u002Fijc.2910340210",{"id":24,"text":278,"url":24,"identifiers":279},"Taylor-Papadimitriou, 1991, Report on the first international workshop on carcinoma-associated mucins, Int. J. Cancer, 49, 1, 10.1002\u002Fijc.2910490102",{"doi":280},"10.1002\u002Fijc.2910490102",{"id":24,"text":282,"url":24,"identifiers":283},"Rye, 1998, ISOBM TD-4 International workshop on monoclonal antibodies against MUC1",{},{"id":24,"text":285,"url":24,"identifiers":286},"Arklie, 1981, Differentiation antigens expressed by epithelial cells in the lactating breast are also detectable in breast cancers, Int. J. Cancer, 28, 23, 10.1002\u002Fijc.2910280105",{"doi":287},"10.1002\u002Fijc.2910280105",{"id":24,"text":289,"url":24,"identifiers":290},"Kufe,, 1984, Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors, Hybridoma, 3, 223, 10.1089\u002Fhyb.1984.3.223",{"doi":291},"10.1089\u002Fhyb.1984.3.223",{"id":24,"text":293,"url":24,"identifiers":294},"Lloyd, 1996, Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines: demonstration of simpler and fewer glycan chains in tumor cells, J. Biol. Chem., 271, 33325, 10.1074\u002Fjbc.271.52.33325",{"doi":295},"10.1074\u002Fjbc.271.52.33325",{"id":24,"text":297,"url":24,"identifiers":298},"Bäckström, 2003, Recombinant MUC1 mucin with a breast cancer-like-O-glycosylation produced in large amounts of Chinese-hamster ovary cells, Biochem. J., 376, 677, 10.1042\u002Fbj20031130",{"doi":299},"10.1042\u002Fbj20031130",{"id":24,"text":301,"url":24,"identifiers":302},"Burchell, 1987, Development and characterisation of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin, Cancer Res., 47, 5476",{},{"id":24,"text":304,"url":24,"identifiers":305},"Perey,, 1992, Tumor selective reactivity of a monoclonal antibody prepared against a recombinant peptide derived from the DF3 human breast carcinoma-associated antigen, Cancer Res., 52, 2563",{},{"id":24,"text":307,"url":24,"identifiers":308},"Rivalland,, 2015, Update on Mucin-1 immunotherapy in cancer: a clinical perspective, Expert Opin. Biol. Ther., 15, 1773, 10.1517\u002F14712598.2015.1088519",{"doi":309},"10.1517\u002F14712598.2015.1088519",{"id":24,"text":311,"url":24,"identifiers":312},"Butts,, 2014, Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial, Lancet Oncol., 15, 59, 10.1016\u002FS1470-2045(13)70510-2",{"doi":313},"10.1016\u002FS1470-2045(13)70510-2",{"id":24,"text":315,"url":24,"identifiers":316},"Quoix,, 2016, TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b\u002F3 trial, Lancet Oncol., 17, 212, 10.1016\u002FS1470-2045(15)00483-0",{"doi":317},"10.1016\u002FS1470-2045(15)00483-0",{"id":24,"text":319,"url":24,"identifiers":320},"Torch,, 2017, Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC, J. Immunother. Cancer, 5, 70, 10.1186\u002Fs40425-017-0274-x",{"doi":321},"10.1186\u002Fs40425-017-0274-x",{"id":24,"text":323,"url":24,"identifiers":324},"https:\u002F\u002Fclinicaltrials.gov\u002Fct2\u002Fshow\u002FNCT02823990",{},{"id":24,"text":326,"url":24,"identifiers":327},"Mitchell,, 2014, A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer, J. Immunother. Cancer, 2, 16, 10.1186\u002F2051-1426-2-16",{"doi":328},"10.1186\u002F2051-1426-2-16",{"id":24,"text":330,"url":24,"identifiers":331},"Gray,, 2014, . Progression-free survival in ovarian cancer patients in second remission with mucin-1 autologous dendritic cell therapy, J. Clin. Oncol., 32, 5504, 10.1200\u002Fjco.2014.32.15_suppl.5504",{"doi":332},"10.1200\u002Fjco.2014.32.15_suppl.5504",{"id":24,"text":334,"url":24,"identifiers":335},"Lepisto,, 2008, A phase I\u002FII study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors, Cancer Ther., 6, 955",{},{"id":24,"text":337,"url":24,"identifiers":338},"Wierecky,, 2006, Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients, Cancer Res., 66, 5910, 10.1158\u002F0008-5472.CAN-05-3905",{"doi":339},"10.1158\u002F0008-5472.CAN-05-3905",{"id":24,"text":341,"url":24,"identifiers":342},"Gong,, 1998, Reversal of tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells, Proc. Natl Acad. Sci. U.S.A., 95, 6279, 10.1073\u002Fpnas.95.11.6279",{"doi":343},"10.1073\u002Fpnas.95.11.6279",{"id":24,"text":345,"url":24,"identifiers":346},"Rosenblatt,, 2016, Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions, Sci. Transl. Med., 8, 368ra171, 10.1126\u002Fscitranslmed.aag1298",{"doi":347},"10.1126\u002Fscitranslmed.aag1298",{"id":24,"text":349,"url":24,"identifiers":350},"Rittig,, 2011, Intradermal vaccinations with
RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients, Mol. Ther., 19, 990, 10.1038\u002Fmt.2010.289",{"doi":351},"10.1038\u002Fmt.2010.289",{"id":24,"text":353,"url":24,"identifiers":354},"Morse,, 2013, A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer, Ann. Surg., 258, 879, 10.1097\u002FSLA.0b013e318292919e",{"doi":355},"10.1097\u002FSLA.0b013e318292919e",{"id":24,"text":357,"url":24,"identifiers":358},"Vassilaros,, 2013, Up to 15-year clinical follow-up of a pilot Phase III immunotherapy study in stage II breast cancer patients using oxidized mannan–MUC1, Immunotherapy, 5, 1177, 10.2217\u002Fimt.13.126",{"doi":359},"10.2217\u002Fimt.13.126",{"id":24,"text":361,"url":24,"identifiers":362},"Shindo,, 2014, Adoptive immunotherapy with MUC1-mRNA transfected dendritic cells and cytotoxic lymphocytes plus gemcitabine for unresectable pancreatic cancer, J. Transl. Med., 12, 175, 10.1186\u002F1479-5876-12-175",{"doi":363},"10.1186\u002F1479-5876-12-175",{"id":24,"text":365,"url":24,"identifiers":366},"Jerome,, 1991, Cytotoxic T-lymphocytes derived from patients with breast adenocarcinoma recognize an epitope present on the protein core of a mucin molecule preferentially expressed by malignant cells, Cancer Res., 51, 2908",{},{"id":24,"text":368,"url":24,"identifiers":369},"Gaidzik,, 2013, The development of synthetic antitumour vaccines from mucin glycopeptide antigens, Chem. Soc. Rev., 42, 4421, 10.1039\u002Fc3cs35470a",{"doi":370},"10.1039\u002Fc3cs35470a",{"id":24,"text":372,"url":24,"identifiers":373},"Kaiser,, 2010, Fully synthetic vaccines consisting of tumor-associated MUC1 glycopeptides and a lipopeptide ligand of the Toll-like receptor 2, Angew. Chem. Int. Ed. Engl., 49, 3688, 10.1002\u002Fanie.201000462",{"doi":374},"10.1002\u002Fanie.201000462",{"id":24,"text":376,"url":24,"identifiers":377},"Palitzsch,, 2016, A synthetic glycopeptide vaccine for the induction of a monoclonal antibody that differentiates between normal and tumor mammary cells and enables the diagnosis of human pancreatic cancer, Angew. Chem. Int. Ed. Engl., 55, 2894, 10.1002\u002Fanie.201509935",{"doi":378},"10.1002\u002Fanie.201509935",{"id":24,"text":380,"url":24,"identifiers":381},"Stergiou,, 2017, Immunization with a synthetic human MUC1 glycopeptide vaccine against tumor-associated MUC1 breaks tolerance in human MUC1 transgenic mice, ChemMedChem., 12, 1424, 10.1002\u002Fcmdc.201700387",{"doi":382},"10.1002\u002Fcmdc.201700387",{"id":24,"text":384,"url":24,"identifiers":385},"Mony,, 2015, Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model, Cancer Immunol. Immunother, 64, 1095, 10.1007\u002Fs00262-015-1712-6",{"doi":386},"10.1007\u002Fs00262-015-1712-6",{"id":24,"text":388,"url":24,"identifiers":389},"Haurum,, 1994, Recognition of carbohydrate by major histocompatibility complex class I-restricted, glycopeptide-specific cytotoxic T lymphocytes, J. Exp. Med., 180, 739, 10.1084\u002Fjem.180.2.739",{"doi":390},"10.1084\u002Fjem.180.2.739",{"id":24,"text":392,"url":24,"identifiers":393},"Karsten,, 2004, Binding patterns of DTR-specific antibodies reveal a glycosylation-conditioned tumor-specific epitope of the epithelial mucin (MUC1), Glycobiology, 14, 681, 10.1093\u002Fglycob\u002Fcwh090",{"doi":394},"10.1093\u002Fglycob\u002Fcwh090",{"id":24,"text":396,"url":24,"identifiers":397},"Danielczyk,, 2006, Pankomab: a potent new generation anti-tumour MUC1 antibody, Cancer Immunol. 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Newer prodrugs for delivering the GSH-based inhibitors into tumour cells include reactive sulphoxide esters that undergo acyl exchange with endogenous GSH to give the inhibitors, and polymethacrylamide esters of the inhibitors that are potentially tumour-selective on the basis of the ‘enhanced permeability and retention effect’. 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