Mannan mucin-1 peptide immunization: influence of cyclophosphamide and the route of injection.
The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.
Karanikas
V
V
Immunology and Vaccine Laboratory, The Austin Research Institute, Victoria, Australia.
Thynne
G
G
Mitchell
P
P
Ong
C S
CS
Gunawardana
D
D
Blum
R
R
Pearson
J
J
Lodding
J
J
Pietersz
G
G
Broadbent
R
R
Tait
B
B
McKenzie
I F
IF
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000097:blood; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular; D016233:Immunotherapy, Active; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation; D008351:Mannans / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D018396:Mucin-1 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D008351:Mannans; D018396:Mucin-1; D011993:Recombinant Fusion Proteins; D003520:Cyclophosphamide