title: Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant.
abstract: We have synthesized various formulations that have potential for active specific immunotherapy (ASI) of human cancers. Sialyl-Tn (STn) is a potentially important target structure for ASI because its expression on mucins is a strong, independent predictor of poor prognosis, suggesting that it may have functional significance in the metastatic process. In this first pilot study of synthetic sialyl-Tn hapten conjugated to keyhole limpet hemocyanin (STn-KLH), with Detox adjuvant, toxicity and humoral immunogenicity were assessed in 12 patients with metastatic breast cancer. Toxicity was minimal, restricted to local cutaneous reactions (apart from transient nausea and vomiting following single low-dose cyclophosphamide treatment). Using STn-conjugated human serum albumin in a solid-phase enzyme-linked immunosorbent assay, it was shown that all patients developed IgM and IgG specific for the synthetic STn hapten. Following immunization, most patients were shown to develop increased titres of complement-mediated cytotoxic antibodies, partially inhibited by synthetic STn hapten, but not by the related TF hapten. We also detected IgM and IgG antibodies reactive with natural STn determinants expressed on ovine submaxillary mucin, the STn specificity of this reactivity being confirmed by hapten inhibition. Evaluation of clinical efficacy in a small pilot study is difficult. Five patients are alive 12 or more months after entry, and another 4 patients are alive 6 or more months after entry into the study. All 3 patients with known widespread bulky disease progressed despite ASI, 2 having died from widespread cancer. Two patients had partial responses, each lasting 6 months. While several patients had disease stability for 3-10 months, 1 patient with pulmonary metastases remains stable 15 months after entry into the program.
authors.affiliation: Cross Cancer Institute, University of Alberta, Edmonton, Canada.
authors.forename: G D
authors.initials: GD
authors.lastname: MacLean
authors.forename: M
authors.initials: M
authors.lastname: Reddish
authors.forename: R R
authors.initials: RR
authors.lastname: Koganty
authors.forename: T
authors.initials: T
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Gandhi
authors.forename: M
authors.initials: M
authors.lastname: Smolenski
authors.forename: J
authors.initials: J
authors.lastname: Samuel
authors.forename: J M
authors.initials: JM
authors.lastname: Nabholtz
authors.forename: B M
authors.initials: BM
authors.lastname: Longenecker
mesh_terms: D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm / Q000276:immunology; D000918:Antibody Specificity; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000008:administration & dosage / Q000276:immunology*; D001943:Breast Neoplasms / Q000628:therapy*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D006001:Glycoconjugates / Q000276:immunology; D006241:Haptens; D006801:Humans; D007114:Immunization; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D006001:Glycoconjugates; D006241:Haptens; C040286:Tn antigen; D003165:Complement System Proteins