Induction and maintenance of monocyte cytotoxicity during treatment with liposomes containing muramyl tripeptide despite tachyphylaxis to the cytokine response.
Monocyte-mediated cytotoxicity (determined in a 72-h111In release assay) and the circulating levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1beta, IL-6, IFN-gamma, C-reactive protein, and beta2-microglobulin were determined in 14 melanoma patients treated with multilamellar vesicle liposomes containing muramyl tripeptide phosphatidylethanolamine, 4 mg twice a week for 12 weeks. Monocyte-mediated cytotoxicity increased 24 h after the first infusion in 9 of 14 patients and had reached maximum levels (mean, 44% +/- 8) in all patients by the sixth week; similar values were observed at the 12th week. Once increased in vivo, peripheral blood monocyte cytotoxicity was not susceptible to any further increase after a subsequent in vitro incubation of the monocytes with liposomes. However, the peripheral blood monocytes which were not cytotoxic in vivo were activated by in vitro incubation with liposomes and not by medium. TNF-alpha and IL-6 peaked 2 h after the first infusion and returned to baseline values at 24 h; they were not significantly increased by subsequent treatments. The induction of fever in patients, observed 2 h after the first infusion, correlated with TNF-alpha and IL-6 levels. Similarly, C-reactive protein levels also increased at 24 h, but only after the first dose. No increase in beta2-microglobulin and IL-1beta levels was observed, and IFN-gamma was never detected in serum. Two patients experienced stable disease lasting 7 and 12 months, and 12 patients progressed. These results show that multilamellar vesicle muramyl tripeptide phosphatidylethanolamine administration activates monocyte cytotoxicity and cytokine production (TNF-alpha, IL-6). Chronic treatment with multilamellar vesicle muramyl tripeptide phosphatidylethanolamine results in tachyphylaxis in terms of cytokine secretion but not cytotoxicity. There was no difference between the maximum cytotoxicity levels obtained in vivo and those obtained in vitro using the same agent. A better understanding of immunoregulation is required for a rational application of this and related immunotherapies.
Galligioni
E
E
Centro di Riferimento Oncologico, Aviano (PN), and Ciba-Geigy, Origgio (VA), Italy.
Favaro
D
D
Santarosa
M
M
Quaia
M
M
Spada
A
A
Freschi
A
A
Alberti
D
D
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D003602:Cytotoxicity, Immunologic; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D004337:Drug Carriers; D007375:Interleukin-1; D015850:Interleukin-6; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; D002097:C-Reactive Protein