lipid-a and Pancreatic-Neoplasms

MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100-amino acid peptide corresponding to five 20-amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 mug) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8(+) T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.

Topics: Aged; Cancer Vaccines; CD8-Positive T-Lymphocytes; Cell Separation; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Glycoproteins; Hepatitis B; Humans; Hypersensitivity, Delayed; Immune System; Immunoglobulin G; Immunoglobulin M; Immunotherapy; Lipid A; Male; Middle Aged; Mucin-1; Pancreatic Neoplasms; Peptides; Radiotherapy, Adjuvant; Saponins; T-Lymphocytes; Time Factors; Treatment Outcome

The effects of a synthetic lipid A on tumor necrosis factor (TNF) production and antitumor activity against human pancreatic cancer cells were investigated. Lipid A (10 mg/kg) was injected into normal rats and mice and serum TNF levels were measured. Lipid A-induced inhibition of Molt 4 and MIA paca-2 cells in culture were measured by counting viable cells. Activity of lipid A against transplanted human pancreatic cancer cells (MIA paca-2, Panc-1) was examined by determining tumor volume, necrosis, and survival rate after intraperitoneal injections of lipid A (10 and 20 mg/kg) over 4 weeks. Serum TNF levels increased 80-fold in rats and 100-fold in mice after intravenous lipid A injection. Although specific tumor growth inhibition by lipid A was not observed in vitro, tumor growth was significantly inhibited, and the survival rate was improved in pancreatic cancer cell-transplanted nude mice treated with lipid A compared with controls. Synthetic lipid A induces TNF production and has antitumor activity against transplanted pancreatic cancer cells. Further studies of this lipid A as an agent for pancreatic cancer are warranted.

Topics: Animals; Antineoplastic Agents; Humans; Lipid A; Mice; Mice, Inbred C3H; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Pancreatic Neoplasms; Rats; Rats, Sprague-Dawley; Reference Values; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The antitumor effect and biological activities of a newly synthesized lipid A analogue (ONO-4007) were investigated in a hamster pancreatic carcinoma model. Marked and dose-dependent inhibition of tumor growth was achieved by i.p. injection twice a week for 3 weeks of 10, 30 or 50 mg/kg of ONO-4007. Endogenous tumor necrosis factor (TNF) activities induced by ONO-4007 were significantly greater in tumor than in serum, spleen and liver. TNF production by macrophages stimulated with ONO-4007 after culture was much greater when culture was performed in the presence of hamster pancreatic carcinoma cells (no cell-to-cell contact). It was further found that the cytotoxic activity of TNF secreted by macrophages cultured with cancer cells was inhibited in the presence of anti-TNF neutralizing antibodies. These findings suggest that ONO-4007 displays antitumor effects by stimulating production of endogenous TNF in tumor macrophages, possibly through activation by soluble macrophage-stimulating factors in cancer cells.

Topics: Animals; Antineoplastic Agents; Cricetinae; Disease Models, Animal; Female; Injections, Intraperitoneal; Lipid A; Macrophages, Peritoneal; Mesocricetus; Neoplasm Transplantation; Pancreatic Neoplasms; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Humans; Lipid A; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Rats; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha