Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
J Clin Invest. 1997 Dec 1; 100(11): 2783–2792.
doi: 10.1172/JCI119825
PMCID: PMC508483
PMID: 9389743

Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein.

V Karanikas, L A Hwang, J Pearson, C S Ong, V Apostolopoulos, H Vaughan, P X Xing, G Jamieson, G Pietersz, B Tait, R Broadbent, G Thynne, and I F McKenzie
Author information Copyright and License information PMC Disclaimer

Abstract

Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.

Full Text

The Full Text of this article is available as a PDF (220K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  • Hilkens J, Ligtenberg MJ, Vos HL, Litvinov SV. Cell membrane-associated mucins and their adhesion-modulating property. Trends Biochem Sci. 1992 Sep;17(9):359–363. [PubMed] [Google Scholar]
  • Apostolopoulos V, McKenzie IF. Cellular mucins: targets for immunotherapy. Crit Rev Immunol. 1994;14(3-4):293–309. [PubMed] [Google Scholar]
  • Apostolopoulos V, Pietersz GA, McKenzie IF. Cell-mediated immune responses to MUC1 fusion protein coupled to mannan. Vaccine. 1996 Jun;14(9):930–938. [PubMed] [Google Scholar]
  • Gendler SJ, Burchell JM, Duhig T, Lamport D, White R, Parker M, Taylor-Papadimitriou J. Cloning of partial cDNA encoding differentiation and tumor-associated mucin glycoproteins expressed by human mammary epithelium. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6060–6064. [PMC free article] [PubMed] [Google Scholar]
  • Siddiqui J, Abe M, Hayes D, Shani E, Yunis E, Kufe D. Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2320–2323. [PMC free article] [PubMed] [Google Scholar]
  • Wreschner DH, Hareuveni M, Tsarfaty I, Smorodinsky N, Horev J, Zaretsky J, Kotkes P, Weiss M, Lathe R, Dion A, et al. Human epithelial tumor antigen cDNA sequences. Differential splicing may generate multiple protein forms. Eur J Biochem. 1990 May 20;189(3):463–473. [PubMed] [Google Scholar]
  • Itzkowitz SH, Yuan M, Montgomery CK, Kjeldsen T, Takahashi HK, Bigbee WL, Kim YS. Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res. 1989 Jan 1;49(1):197–204. [PubMed] [Google Scholar]
  • Xing PX, Prenzoska J, McKenzie IF. Epitope mapping of anti-breast and anti-ovarian mucin monoclonal antibodies. Mol Immunol. 1992 May;29(5):641–650. [PubMed] [Google Scholar]
  • Xing PX, Tjandra JJ, Stacker SA, Teh JG, Thompson CH, McLaughlin PJ, McKenzie IF. Monoclonal antibodies reactive with mucin expressed in breast cancer. Immunol Cell Biol. 1989 Jun;67(Pt 3):183–195. [PubMed] [Google Scholar]
  • Gendler SJ, Spicer AP. Epithelial mucin genes. Annu Rev Physiol. 1995;57:607–634. [PubMed] [Google Scholar]
  • Jerome KR, Barnd DL, Bendt KM, Boyer CM, Taylor-Papadimitriou J, McKenzie IF, Bast RC, Jr, Finn OJ. 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. 1991 Jun 1;51(11):2908–2916. [PubMed] [Google Scholar]
  • Barnd DL, Kerr LA, Metzgar RS, Finn OJ. Human tumor-specific cytotoxic T cell lines generated from tumor-draining lymph node infiltrate. Transplant Proc. 1988 Apr;20(2):339–341. [PubMed] [Google Scholar]
  • Jerome KR, Domenech N, Finn OJ. Tumor-specific cytotoxic T cell clones from patients with breast and pancreatic adenocarcinoma recognize EBV-immortalized B cells transfected with polymorphic epithelial mucin complementary DNA. J Immunol. 1993 Aug 1;151(3):1654–1662. [PubMed] [Google Scholar]
  • Ioannides CG, Fisk B, Jerome KR, Irimura T, Wharton JT, Finn OJ. Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. J Immunol. 1993 Oct 1;151(7):3693–3703. [PubMed] [Google Scholar]
  • Takahashi T, Makiguchi Y, Hinoda Y, Kakiuchi H, Nakagawa N, Imai K, Yachi A. Expression of MUC1 on myeloma cells and induction of HLA-unrestricted CTL against MUC1 from a multiple myeloma patient. J Immunol. 1994 Sep 1;153(5):2102–2109. [PubMed] [Google Scholar]
  • Barnd DL, Lan MS, Metzgar RS, Finn OJ. Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7159–7163. [PMC free article] [PubMed] [Google Scholar]
  • Apostolopoulos V, Xing PX, McKenzie IF. Murine immune response to cells transfected with human MUC1: immunization with cellular and synthetic antigens. Cancer Res. 1994 Oct 1;54(19):5186–5193. [PubMed] [Google Scholar]
  • Apostolopoulos V, Pietersz GA, Loveland BE, Sandrin MS, McKenzie IF. Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10128–10132. [PMC free article] [PubMed] [Google Scholar]
  • Apostolopoulos V, Loveland BE, Pietersz GA, McKenzie IF. CTL in mice immunized with human mucin 1 are MHC-restricted. J Immunol. 1995 Dec 1;155(11):5089–5094. [PubMed] [Google Scholar]
  • Apostolopoulos V, Xing PX, Trapani JA, McKenzie IF. Production of anti-breast cancer monoclonal antibodies using a glutathione-S-transferase-MUC1 bacterial fusion protein. Br J Cancer. 1993 Apr;67(4):713–720. [PMC free article] [PubMed] [Google Scholar]
  • Hodges RS, Merrifield RB. Monitoring of solid phase peptide synthesis by an automated spectrophotometric picrate method. Anal Biochem. 1975 May 12;65(1-2):241–272. [PubMed] [Google Scholar]
  • Sandrin MS, Vaughan HA, Xing PX, McKenzie IF. Natural human anti-Gal alpha(1,3)Gal antibodies react with human mucin peptides. Glycoconj J. 1997 Jan;14(1):97–105. [PubMed] [Google Scholar]
  • MacLean GD, Bowen-Yacyshyn MB, Samuel J, Meikle A, Stuart G, Nation J, Poppema S, Jerry M, Koganty R, Wong T, et al. Active immunization of human ovarian cancer patients against a common carcinoma (Thomsen-Friedenreich) determinant using a synthetic carbohydrate antigen. J Immunother (1991) 1992 May;11(4):292–305. [PubMed] [Google Scholar]
  • Geysen HM, Rodda SJ, Mason TJ, Tribbick G, Schoofs PG. Strategies for epitope analysis using peptide synthesis. J Immunol Methods. 1987 Sep 24;102(2):259–274. [PubMed] [Google Scholar]
  • Karlsson R, Michaelsson A, Mattsson L. Kinetic analysis of monoclonal antibody-antigen interactions with a new biosensor based analytical system. J Immunol Methods. 1991 Dec 15;145(1-2):229–240. [PubMed] [Google Scholar]
  • Fisk B, Ioannides CG, Aggarwal S, Wharton JT, O'Brian CA, Restifo N, Glisson BS. Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line. Lymphokine Cytokine Res. 1994 Apr;13(2):125–131. [PubMed] [Google Scholar]
  • Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res. 1994 Jun 1;54(11):2856–2860. [PubMed] [Google Scholar]
  • Apostolopoulos V, McKenzie IF, Pietersz GA. Breast cancer immunotherapy: current status and future prospects. Immunol Cell Biol. 1996 Oct;74(5):457–464. [PubMed] [Google Scholar]
  • Longenecker BM, Reddish M, Koganty R, MacLean GD. Immune responses of mice and human breast cancer patients following immunization with synthetic sialyl-Tn conjugated to KLH plus detox adjuvant. Ann N Y Acad Sci. 1993 Aug 12;690:276–291. [PubMed] [Google Scholar]
  • MacLean GD, Reddish M, Koganty RR, Wong T, Gandhi S, Smolenski M, Samuel J, Nabholtz JM, Longenecker BM. Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. Cancer Immunol Immunother. 1993;36(4):215–222. [PMC free article] [PubMed] [Google Scholar]
  • O'Boyle KP, Zamore R, Adluri S, Cohen A, Kemeny N, Welt S, Lloyd KO, Oettgen HF, Old LJ, Livingston PO. Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn. Cancer Res. 1992 Oct 15;52(20):5663–5667. [PubMed] [Google Scholar]
  • MacLean GD, Reddish MA, Koganty RR, Longenecker BM. Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother Emphasis Tumor Immunol. 1996 Jan;19(1):59–68. [PubMed] [Google Scholar]
  • Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med. 1994 Nov 24;331(21):1428–1436. [PubMed] [Google Scholar]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed] [Google Scholar]
  • Rughetti A, Turchi V, Ghetti CA, Scambia G, Panici PB, Roncucci G, Mancuso S, Frati L, Nuti M. Human B-cell immune response to the polymorphic epithelial mucin. Cancer Res. 1993 Jun 1;53(11):2457–2459. [PubMed] [Google Scholar]
  • von Mensdorff-Pouilly S, Gourevitch MM, Kenemans P, Verstraeten AA, Litvinov SV, van Kamp GJ, Meijer S, Vermorken J, Hilgers J. Humoral immune response to polymorphic epithelial mucin (MUC-1) in patients with benign and malignant breast tumours. Eur J Cancer. 1996 Jul;32A(8):1325–1331. [PubMed] [Google Scholar]
  • Gourevitch MM, von Mensdorff-Pouilly S, Litvinov SV, Kenemans P, van Kamp GJ, Verstraeten AA, Hilgers J. Polymorphic epithelial mucin (MUC-1)-containing circulating immune complexes in carcinoma patients. Br J Cancer. 1995 Oct;72(4):934–938. [PMC free article] [PubMed] [Google Scholar]
  • Petrarca C, Rughetti A, Rahimi H, D'Agostini F, Turchi V, Apollonj Ghetti C, Scambia G, Frati L, Nuti M. Human antibodies against the polymorphic epithelial mucin in ovarian cancer patients recognise a novel sequence in the tandem repeat region. Eur J Cancer. 1996 Nov;32A(12):2155–2163. [PubMed] [Google Scholar]
  • Burchell J, Taylor-Papadimitriou J, Boshell M, Gendler S, Duhig T. A short sequence, within the amino acid tandem repeat of a cancer-associated mucin, contains immunodominant epitopes. Int J Cancer. 1989 Oct 15;44(4):691–696. [PubMed] [Google Scholar]
  • Nakao M, Yamana H, Imai Y, Toh Y, Toh U, Kimura A, Yanoma S, Kakegawa T, Itoh K. HLA A2601-restricted CTLs recognize a peptide antigen expressed on squamous cell carcinoma. Cancer Res. 1995 Oct 1;55(19):4248–4252. [PubMed] [Google Scholar]
  • Ressing ME, van Driel WJ, Celis E, Sette A, Brandt MP, Hartman M, Anholts JD, Schreuder GM, ter Harmsel WB, Fleuren GJ, et al. Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-A *0201-restricted E7-encoded epitope. Cancer Res. 1996 Feb 1;56(3):582–588. [PubMed] [Google Scholar]
  • Rammensee HG, Friede T, Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. [PubMed] [Google Scholar]
  • Redfield RR, Birx DL, Ketter N, Tramont E, Polonis V, Davis C, Brundage JF, Smith G, Johnson S, Fowler A, et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. Military Medical Consortium for Applied Retroviral Research. N Engl J Med. 1991 Jun 13;324(24):1677–1684. [PubMed] [Google Scholar]
  • Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y, et al. Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer. 1995 Dec 11;63(6):883–885. [PubMed] [Google Scholar]
  • Goydos JS, Elder E, Whiteside TL, Finn OJ, Lotze MT. A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma. J Surg Res. 1996 Jun;63(1):298–304. [PubMed] [Google Scholar]
  • Topfer F, Gordon T, McCluskey J. Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A). Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):875–879. [PMC free article] [PubMed] [Google Scholar]
  • Disis ML, Calenoff E, McLaughlin G, Murphy AE, Chen W, Groner B, Jeschke M, Lydon N, McGlynn E, Livingston RB, et al. Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res. 1994 Jan 1;54(1):16–20. [PubMed] [Google Scholar]
  • Houbiers JG, Nijman HW, van der Burg SH, Drijfhout JW, Kenemans P, van de Velde CJ, Brand A, Momburg F, Kast WM, Melief CJ. In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur J Immunol. 1993 Sep;23(9):2072–2077. [PubMed] [Google Scholar]
  • Fairchild PJ, Wraith DC. Lowering the tone: mechanisms of immunodominance among epitopes with low affinity for MHC. Immunol Today. 1996 Feb;17(2):80–85. [PubMed] [Google Scholar]
  • Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. [PubMed] [Google Scholar]
Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation
-