Mannan mucin-1 peptide immunization: Influence of cyclophosphamide and theroute of injection

The mucin MUC1 is greatly increased in breast cancer and is a potential tar get for immunotherapy. In mice, MUC1 conjugated to oxidized mannan (MUC1-ma nnan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this bas is, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUC1. Forty-o ne patients with metastatic or locally advanced carcinoma of the breast (tr ial 1), colon (trial 2), and various adenocarcinomas (trial 3) received inc reasing doses of M-FP (1 to 300 mug). The immunizations were given at weekl y intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide ( to increase cellular immunity) was given on weeks 1 and 3. M-FP was given i ntramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effect s occurred, and delayed-type hypersensitivity responses were present only a s a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with th e intraperitoneal route yielding approximately 10-fold higher responses. Ce llular responses (proliferation, cytotoxic T cells, or CD8 T cells secretin g tumor necrosis factor-alpha and interferon-gamma in response to MUC1 stim ulation in vitro) were found in 28% of the patients, which was similar to t hat seen without cyclophosphamide. In most patients, disease progressed, bu t in five it remained stable. In addition, there were no objective response s. M-FP is not toxic and induces immune responses that were amplified by th e intraperitoneal route of immunization. Cyclophosphamide was of no benefit .