A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma.
We tested a 105 amino acid synthetic mucin MUC-1 peptide that has 5 repeated immunodominant epitopes to evaluate toxicity and detect mucin-specific immune responses in patients with adenocarcinoma. We also studied the enhancement of these responses by vaccinating patients with the synthetic mucin peptide admixed with BCG. Mucins are glycoproteins present on the luminal surface of ductal epithelial cells and on tumors derived from them. The MUC-1 mucin is hypoglycosylated and nonpolarized on tumors and this exposes epitopes that can stimulate cytotoxic T-Cells (CTL). We vaccinated 63 patients with 100 micrograms of the 105aa mucin peptide mixed with BCG. Two additional vaccinations were given at 3-week intervals. All patients were able to tolerate vaccination, with most experiencing local ulceration at the vaccination site. All patients underwent hypersensitivity (DTH) testing with the 105aa and shorter mucin peptides, prior to vaccination. DTH responses were evaluated at 48 hr and the sites of highest peptide concentration were biopsied. Only 3 patients had a strong skin response to the long peptide. Examination of 55 biopsies showed intense T-Cell infiltration in 37 patients and lesser infiltration in 7. Seven of 22 patients tested had a 2- to 4-fold increase in mucin-specific CTLp. Serum levels of IL-6 were measured sequentially using the B9 hybridoma bioassay. Increasing serum levels of IL-6 correlated with constitutional symptoms (significance 0.001) and hypoalbuminemia (significance 0.007) but not with the extent of skin breakdown at vaccination sites. We conclude that mucin vaccination is safe and might serve to enhance specific responses to tumor antigens. IL-6 may be responsible for the constitution symptoms and hypoalbuminemia in these patients.
Goydos
J S
JS
University of Pittsburgh School of Medicine, Department of Surgery, Pennsylvania 15261, USA.
Elder
E
E
Whiteside
T L
TL
Finn
O J
OJ
Lotze
M T
MT
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000009:adverse effects; D001500:BCG Vaccine; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D000939:Epitopes / Q000009:adverse effects; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000009:adverse effects*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014614:Vaccines, Synthetic / Q000009:adverse effects*
D000951:Antigens, Neoplasm; D001500:BCG Vaccine; D000939:Epitopes; D015850:Interleukin-6; D018396:Mucin-1; D014614:Vaccines, Synthetic