ImMucin: A novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors

• Published in: Vaccine 2011-06, Vol.29 (29-30), p.4676-4686
• Main Authors: Kovjazin, Riva, Volovitz, Ilan, Kundel, Yulia, Rosenbaum, Eli, Medalia, Gal, Horn, Galit, Smorodinsky, Nechama I, Brenner, Baruch, Carmon, Lior
• Format: Article
• Language: English
• Subjects: Aged; alleles; Allergy and Immunology; Animals; Applied microbiology; Biological and medical sciences; Cancer; Cancer vaccine; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8-positive T-lymphocytes; Cell Proliferation; Colon; Cytotoxicity; Cytotoxicity, Immunologic; Disease Models, Animal; epitopes; Female; Fundamental and applied biological sciences. Psychology; Gene amplification; granulocyte-macrophage colony-stimulating factor; Histocompatibility Antigens - immunology; Histocompatibility Antigens - metabolism; Humans; Immunization; Immunotherapy; Immunotherapy - methods; interferon-gamma; interleukin-2; Leukocytes, Mononuclear - immunology; Lymphocytes; Male; mammary neoplasms (animal); Medical sciences; metastasis; MHC class I; MHC class II; Mice; Mice, Inbred BALB C; Mice, Transgenic; Microbiology; Middle Aged; MUC1; Mucin-1 - biosynthesis; Mucin-1 - immunology; Neoplasms - therapy; patients; Peptides; Protein Binding; Protein expression; Rodent Diseases - therapy; Signal peptide; Studies; subunit vaccines; Surgery; Survival Analysis; synthetic peptides; transgenic animals; Tumors; vaccination; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Whites
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2011.04.103

Abstract An optimal cancer vaccine should be able to induce highly potent, long-lasting, tumor-specific responses in the majority of the cancer patient population. One approach for achieving this is to use synthetic peptide vaccines derived from widely expressed tumor-associated antigens, that promiscuously bind multiple MHC class I and class II alleles. MUC1-SP-L (ImMucin, VXL100) is a 21mer peptide encoding the complete signal peptide domain of MUC1, a tumor-associated antigen expressed by over 90% of solid and non-solid tumors. MUC1-SP-L was predicted in silico to bind various MHC class I and MHC class II alleles, covering the majority of the Caucasian population. PBLs obtained from 13 naïve donors all proliferated, with a Stimulation Index (SI ≥ 2), to the MUC1-SP-L peptide, producing mixed CD4+ and CD8+ responses. Similar results were manifested by MUC1-SP-L in PBLs derived from 9 of 10 cancer patients with MUC1 positive tumors. CD4+ and CD8+ T cell populations exhibited CD45RO memory markers and secreted IFN-gamma and IL-2 following stimulation with MUC1-SP-L. These T cells also exhibited proliferation to the MUC1-SP-L inner 9mer epitopes and cytotoxicity against tumor cell lines expressing MUC1 and a concordant MHC class I allele. Cytotoxicity to MUC1-expressing human and murine tumors was shown also in T cells obtained from HLA-A2 transgenic mice and BALB/c syngeneic mice immunized with the MUC1-SP-L and GM-CSF. In an immunotherapy model, BALB/c mice inoculated with metastatic MUC1 transfected murine DA3 mammary tumor cells, exhibited significantly prolonged survival following vaccination with MUC1-SP-L. Our results indicate superior immunological and anti-tumor properties of MUC1-SP-L compared to previously published MUC1-derived epitopes.