title: A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.
abstract: Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.
authors.affiliation: ICRF Clinical Oncology Unit, Guy's Hospital, London.
authors.forename: D W
authors.initials: DW
authors.lastname: Miles
authors.forename: K E
authors.initials: KE
authors.lastname: Towlson
authors.forename: R
authors.initials: R
authors.lastname: Graham
authors.forename: M
authors.initials: M
authors.lastname: Reddish
authors.forename: B M
authors.initials: BM
authors.lastname: Longenecker
authors.forename: J
authors.initials: J
authors.lastname: Taylor-Papadimitriou
authors.forename: R D
authors.initials: RD
authors.lastname: Rubens
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000097:blood; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006433:Hemocyanins / Q000627:therapeutic use*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D016233:Immunotherapy, Active; D008875:Middle Aged; D012680:Sensitivity and Specificity
chemical_list: D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C055491:sialosyl-Tn antigen; D003520:Cyclophosphamide; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin