Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma.
BACKGROUND
Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipeptide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma.


OBJECTIVE
Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties.


METHODS
Patients were randomly assigned to 1- or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12-24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-alpha (TNF-alpha), neopterin, interleukin-1-beta, interleukin-6 (IL-6), and beta 2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mononuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells.


RESULTS
MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-alpha levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-alpha levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in beta 2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1 beta were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes, 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population.


CONCLUSIONS
We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified.


CONCLUSIONS
In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting.
Liebes
L
L
Department of Medicine, New York University Medical Center, NY 10016.
Walsh
C M
CM
Chachoua
A
A
Oratz
R
R
Richards
D
D
Hochster
H
H
Peace
D
D
Marino
D
D
Alba
S
S
Le Sher
D
D
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D003602:Cytotoxicity, Immunologic; D004341:Drug Evaluation; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D008545:Melanoma / Q000628:therapy*; D009000:Monocytes / Q000276:immunology*; D009362:Neoplasm Metastasis; D019798:Neopterin; D010714:Phosphatidylethanolamines / Q000627:therapeutic use*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D015850:Interleukin-6; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; C037144:mifamurtide; D001708:Biopterins; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019798:Neopterin