Latest developments in MUC1 immunotherapy

Joyce Taylor-Papadimitriou, Joy M Burchell, Rosalind Graham, Richard Beatson, Joyce Taylor-Papadimitriou, Joy M Burchell, Rosalind Graham, Richard Beatson

Abstract

Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. 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. ppbiost;46/3/659/BST20170400CF1F1BST-2017-0400CF1Figure 1.Number of MUC1-targeted trials initiated each year.

Keywords: MUC1; cancer; immunotherapy.

Conflict of interest statement

J.B. is a consultant for Palleon Pharmaceuticals. All other authors declare no conflicts of interest.

© 2018 The Author(s).

Figures

Figure 1.. Number of MUC1-targeted trials initiated…
Figure 1.. Number of MUC1-targeted trials initiated each year.
Figure 2.. The structure of the MUC1…
Figure 2.. The structure of the MUC1 mucin.
During translation, MUC1 is cleaved into two domains, MUC1-N and MUC1-C. MUC1-N consists predominantly of the TR domain and the sequence of a single repeat is illustrated. The TR domain is glycosylated with O-linked glycans (in red) and each repeat has five potential sites shown in bold. There are also sites for O-linked glycosylation in the degenerate TRs located to the N- and C-termini of the repeats. There are five potential sites for N-linked glycosylation close to the membrane (in black). MUC1-C consists of 58 amino acids of the external domain, the transmembrane domain (in blue, 28 aa) and the cytoplasmic domain (MUC1-CD, 72 aa). Within the CD1 domain, the CQC trimer is responsible for homodimerization. There are many phosphorylation sites within the CD domain and two of these are indicated. The CQC containing peptide (GO-232) targets the homodimerization domain.
Figure 3.. Simplified pathways of mucin-type O-linked…
Figure 3.. Simplified pathways of mucin-type O-linked glycosylation in normal and malignant breast epithelial cells.
The Tn glycan can be carried on MUC1 expressed by a high proportion of breast cancers. The STn glycan is found in ∼25% of breast cancers, while ST is more commonly expressed. The unsialylated core 1 (T) is also widely found on MUC1 expressed by breast cancers. In contrast, the glycans found on MUC1 expressed by normal mammary epithelial cells are core 2 based.
Figure 4.. Current and potential clinical approaches…
Figure 4.. Current and potential clinical approaches targeting MUC1 in cancer.
Current strategies fall into six broad categories (as shown in the boxes) ranging from preclinical to Phase III. The bullet point within each box gives an example of that category of immunotherapy. To date, no therapeutic targeting MUC1 has been approved for general use. GM, genetically modified; DC, dendritic cell; APC, antigen-presenting cell; NK, natural killer.

References

    1. Gendler S.J., Burchell J.M., Duhig T., Lamport D., White R., Parker M. et al. (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, 6060–6064 10.1073/pnas.84.17.6060
    1. Lan M.S., Batra S.K., Qi W.N., Metzgar R.S. and Hollingsworth M.A. (1990) Cloning and sequencing of a human pancreatic tumor mucin cDNA. J. Biol. Chem. 265, 15294–15299 PMID:
    1. Ligtenberg M.J., Vos H.L., Gennissen A.M. and Hilkens J. (1990) Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini. J. Biol. Chem. 265, 5573–5578 PMID:
    1. Siddiqui J., Abe M., Hayes D., Shani E., Yunis E. and Kufe D. (1988) Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc. Natl Acad. Sci. U.S.A. 85, 2320–2323 10.1073/pnas.85.7.2320
    1. Baruch A., Hartmann M., Yoeli M., Adereth Y., Greenstein S., Stadler Y. et al. (1999) The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein. Cancer Res. 59, 1552–1561 PMID:
    1. Julian, J., Dharmaraj, N. and Carson, D.D. (2009) MUC1 is a substrate for γ-secretase. J. Cell Biochem. 108, 802–815 10.1002/jcb.22292
    1. Kufe, D.W. (2013) MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 32, 1073–1081 10.1038/onc.2012.158
    1. Kufe, D.W. (2009) Mucins in cancer: function, prognosis and therapy. Nat. Rev. Cancer 9, 874–885 10.1038/nrc2761
    1. Taylor-Papadimitriou J., Peterson J.A., Arklie J., Burchell J., Ceriani R.L. and Bodmer W.F. (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, 17–21 10.1002/ijc.2910280104
    1. Hilkens, J., Buijs, F., Hilgers, J., Hageman, P., Calafat, J., Sonnenberg, A. et al. (1984) Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumors. Int. J. Cancer 34, 197–206 10.1002/ijc.2910340210
    1. Taylor-Papadimitriou J. (1991) Report on the first international workshop on carcinoma-associated mucins. Int. J. Cancer 49, 1–5 10.1002/ijc.2910490102
    1. Rye P.D. and Price M.R. (1998) ISOBM TD-4 International workshop on monoclonal antibodies against MUC1. Workshop, San Diego, CA, November 1996 ISBN: 978-3-8055-6597-4
    1. Arklie J., Taylor-Papadimitriou J., Bodmer W.F., Egan M. and Millis R. (1981) Differentiation antigens expressed by epithelial cells in the lactating breast are also detectable in breast cancers. Int. J. Cancer 28, 23–29 10.1002/ijc.2910280105
    1. Kufe, D., Inghirami, G., Abe, M., Hayes, D., Justi-Wheeler, H. and Schlom, J. (1984) Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma 3, 223–232 10.1089/hyb.1984.3.223
    1. Lloyd K.O., Burchell J., Kudryashov V., Yin B.W.T. and Taylor-Papadimitriou J. (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, 33325–33334 10.1074/jbc.271.52.33325
    1. Bäckström M., Link T., Olson F.J., Karlsson H., Graham R., Picco G. et al. (2003) Recombinant MUC1 mucin with a breast cancer-like-O-glycosylation produced in large amounts of Chinese-hamster ovary cells. Biochem. J. 376, 677–686 10.1042/bj20031130
    1. Burchell J., Gendler S., Taylor-Papadimitriou J., Girling A., Lewis A., Millis R. et al. (1987) Development and characterisation of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Res. 47, 5476–5482 PMID:
    1. Perey, L., Hayes, D.F., Maimonis, P., Abe, M., O'Hara, C. and Kufe, D.W. (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, 2563–2568 PMID:
    1. Rivalland, G., Loveland, B. and Mitchell, P. (2015) Update on Mucin-1 immunotherapy in cancer: a clinical perspective. Expert Opin. Biol. Ther. 15, 1773–1787 10.1517/14712598.2015.1088519
    1. Butts, C., Socinski, M.A., Mitchell, P.L., Thatcher, N., Havel, L., Krzakowski, M. et al. (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, 59–68 10.1016/S1470-2045(13)70510-2
    1. Quoix, E., Lena, H., Losonczy, G., Forget, F., Chouaid, C., Papai, Z. et al. (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/3 trial. Lancet Oncol. 17, 212–223 10.1016/S1470-2045(15)00483-0
    1. Torch, C., Bastien, B., Barraud, L., Grellier, B., Nourtier, V., Gantzer, M. et al. (2017) Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC. J. Immunother. Cancer 5, 70 10.1186/s40425-017-0274-x
    1. .
    1. Mitchell, P.L., Quinn, M.A., Grant, P.T., Allen, D.G., Jobling, T.W., White, S.C. et al. (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 10.1186/2051-1426-2-16
    1. Gray, H.J. and Gargosky, S.E. (2014) CAN-003 Study Team. Progression-free survival in ovarian cancer patients in second remission with mucin-1 autologous dendritic cell therapy. J. Clin. Oncol. 32(15 Suppl), 5504 10.1200/jco.2014.32.15_suppl.5504
    1. Lepisto, A.J., Moser, A.J., Zeh, H., Lee K., Bartlett D., McKolanis J.R. et al. (2008) A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 6, 955–964 PMID:
    1. Wierecky, J., Müller, M.R., Wirths, S., Halder-Oehler E., Dörfel D., Schmidt S.M. et al. (2006) Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res. 66, 5910–5918 10.1158/0008-5472.CAN-05-3905
    1. Gong, J., Chen, D., Kashiwaba, M., Li, Y., Chen, L., Takeuchi, H. et al. (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, 6279–6283. Point 2 Insert in textp3 under Phase1/II trials DCs 10.1073/pnas.95.11.6279
    1. Rosenblatt, J., Stone, R.M., Uhl, L., Neuberg, D., Joyce, R., Levine, J.D. et al. (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/scitranslmed.aag1298
    1. Rittig, S.M., Haentschel, M., Weimer, K.J., Heine A., Muller M.R., Brugger W. et al. (2011) Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol. Ther. 19, 990–999 10.1038/mt.2010.289
    1. Morse, M.A., Niedzwiecki, D., Marshall, J.L., Garrett C., Chang D.Z., Aklilu M. et al. (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, 879–886 10.1097/SLA.0b013e318292919e
    1. Vassilaros, S., Tsibanis, A., Tsikkinis, A., Pietersz, G.A., McKenzie, I.F. and Apostolopoulos, V. (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, 1177–1182 10.2217/imt.13.126
    1. Shindo, Y., Hazama, S., Maeda, Y., Matsui, H., Iida, M., Suzuki, N. et al. (2014) Adoptive immunotherapy with MUC1-mRNA transfected dendritic cells and cytotoxic lymphocytes plus gemcitabine for unresectable pancreatic cancer. J. Transl. Med. 12, 175 10.1186/1479-5876-12-175
    1. Jerome, K.R., Barnd, D.L., Bendt, K.M., Boyer, C.M., Taylor-Papadimitriou, J., McKenzie, I.F. et al. (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, 2908–2916 PMID:
    1. Gaidzik, N., Westerlind, U. and Kunz, H. (2013) The development of synthetic antitumour vaccines from mucin glycopeptide antigens. Chem. Soc. Rev. 42, 4421–4442 10.1039/c3cs35470a
    1. Kaiser, A., Gaidzik, N., Becker, T., Menge, C., Groh, K., Cai, H. et al. (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, 3688–3692 10.1002/anie.201000462
    1. Palitzsch, B., Gaidzik, N., Stergiou, N., Stahn, S., Hartmann, S., Gerlitzki, B. et al. (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, 2894–2898 10.1002/anie.201509935
    1. Stergiou, N., Glaffig, M., Jonuleit, H., Schmitt, E. and Kunz, H. (2017) Immunization with a synthetic human MUC1 glycopeptide vaccine against tumor-associated MUC1 breaks tolerance in human MUC1 transgenic mice. ChemMedChem. 12, 1424–1428 10.1002/cmdc.201700387
    1. Mony, J.T., Zhang, L., Ma, T., Grabosch, S., Tirodkar, T.S., Brozick, J. et al. (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, 1095–1108 10.1007/s00262-015-1712-6
    1. Haurum, J.S., Arsequell, G., Lellouch, A.C., Wong, S.Y., Dwek, R.A., McMichael, A.J. et al. (1994) Recognition of carbohydrate by major histocompatibility complex class I-restricted, glycopeptide-specific cytotoxic T lymphocytes. J. Exp. Med. 180, 739–744 10.1084/jem.180.2.739
    1. Karsten, U., Serttas, N., Paulsen, H., Danielczyk, A. and Goletz, S. (2004) Binding patterns of DTR-specific antibodies reveal a glycosylation-conditioned tumor-specific epitope of the epithelial mucin (MUC1). Glycobiology 14, 681–692 10.1093/glycob/cwh090
    1. Danielczyk, A., Stahn, R., Faulstich, D., Löffler, A., Märten, A., Karsten, U. et al. (2006) Pankomab: a potent new generation anti-tumour MUC1 antibody. Cancer Immunol. Immunother. 55, 1337–1347 10.1007/s00262-006-0135-9
    1. Fiedler, W., DeDosso, S., Cresta, S., Weidmann, J., Tessari, A., Salzberg, M. et al. (2016) A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. Eur. J. Cancer 63, 55–63 10.1016/j.ejca.2016.05.003
    1. Wilkie, S., Picco, G., Foster, J., Davies, D.M., Julien, S., Cooper, L. et al. (2008) Retargeting of human T cells to tumour-associated MUC1: the evolution of a chimeric antigen receptor. J. Immunol. 180, 4901–4909 10.4049/jimmunol.180.7.4901
    1. Posey A.D. Jr, Schwab, R.D., Boesteanu, A.C., Steentoft, C., Mandel, U., Engels, B. et al. (2016) Engineered CAR T cells targeting the cancer-associated Tn-Glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity 44, 1444–1454 10.1016/j.immuni.2016.05.014
    1. Sørensen A.L., Reis C.A., Tarp M.A., Mandel U., Ramachandran K., Sankaranarayan V. et al. (2006) Chemoenzymatically synthesized multimeric Tn/STn-MUC1 glycopeptides elicit cancer specific anti-MUC1 antibody responses and override tolerance. Glycobiology 16, 96–107 10.1093/glycob/cwj044
    1. Tarp M.A., Sørensen A.L., Mandel U., Paulsen H., Burchell J., Taylor-Papadimitriou J. et al. (2007) Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat. Glycobiology 17, 197–209 10.1093/glycob/cwl061
    1. Correa I., Plunkett T., Vlad A., Mungul A., Candelora-Kettel J., Burchell J.M. et al. (2003) Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T cell migration. Immunology 108, 32–41 10.1046/j.1365-2567.2003.01562.x
    1. Gavrill, A. (2017) Chimeric Antigen Receptor (CAR) T-cell Immunotherapy for MUC1-positive Breast Cancer PhD Thesis, Kings College London
    1. Vlad, A.M., Muller, S., Cudic, M., Paulsen, H., Otvos L. Jr, Hanisch, F.G. et al. (2002) Complex carbohydrates are not removed during processing of glycoproteins by dendritic cells: processing of tumor antigen MUC1 glycopeptides for presentation to major histocompatibility complex class II-restricted T cells. J. Exp. Med. 196, 1435–1446 10.1084/jem.20020493
    1. Ryan, S.O., Vlad, A.M., Islam, K., Gariépy, J. and Finn, O.J. (2009) Tumor-associated MUC1 glycopeptide epitopes are not subject to self-tolerance and improve responses to MUC1 peptide epitopes in MUC1 transgenic mice. Biol. Chem. 390, 611–618 10.1515/BC.2009.070
    1. Scheid, E., Major, P., Bergeron, A., Finn, O.J., Salter, R.D., Eady, R. et al. (2016) Tn-MUC1 DC vaccination of rhesus macaques and a phase I/II trial in patients with nonmetastatic castrate-resistant prostate cancer. Cancer Immunol. Res. 4, 881–892 10.1158/2326-6066.CIR-15-0189
    1. Beatson, R., Tajadura-Ortega, V., Achkova, D., Picco, G., Tsourouktsoglou, T.D., Klausing, S. et al. (2016) The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9. Nat. Immunol. 17, 1273–1281 10.1038/ni.3552
    1. Pyzer, A.R., Stroopinsky, D., Rajabi, H., Washington, A., Tagde, A., Coll, M. et al. (2017) MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood 129, 1791–1801 10.1182/blood-2016-07-730614
    1. Rajabi, H. and Kufe, D. (2017) MUC1-C oncoprotein integrates a program of EMT, epigenetic reprogramming and immune evasion in human carcinomas. Biochim. Biophys. Acta 1868, 117–122 10.1016/j.bbcan.2017.03.003
    1. Tagde, A., Rajabi, H., Bouillez, A., Alam, M., Gali, R., Bailey, S. et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127, 2587–2597 10.1182/blood-2015-07-659151
    1. Tagde, A., Markert, T., Rajabi, H., Hiraki, M., Alam, M., Bouillez, A. et al. (2017) Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma. Oncotarget 8, 69237–69249 10.18632/oncotarget.20144
    1. Bouillez, A., Rajabi, H., Jin, C., Samur, M., Tagde, A., Alam, M. et al. (2017) MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene 36, 4037–4046 10.1038/onc.2017.47
    1. Bouillez, A., Adeegbe, D., Jin, C., Hu, X., Tagde, A., Alam, M. et al. (2017) MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer. Oncoimmunology 6, e1338998 10.1080/2162402X.2017.1338998 eCollection 2017
    1. Pyzer, A.R., Stroopinsky, D., Rosenblatt, J., Anastasiadou, E., Rajabi, H., Washington, A. et al. (2017) MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia 31, 2780–2790 10.1038/leu.2017.163
    1. Maeda, T., Hiraki, M., Jin, C., Rajabi, H., Tagde, A., Alam, M. et al. (2018) MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Res. 78, 205–215 10.1158/0008-5472.CAN-17-1636
    1. Miles, D., Roché, H., Martin, M., Perren, T.J., Cameron, D.A., Glaspy, J. et al. ; Theratope® Study Group (2011) Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer. Oncologist 16, 1092–1100 10.1634/theoncologist.2010-0307
    1. Verheijen, R.H., Massuger, L.F., Benigno, B.B., Epenetos, A.A., Lopes, A., Soper, J.T. et al. (2006) Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J. Clin. Oncol. 24, 571–578 10.1200/JCO.2005.02.5973

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