Modulation of monocyte functions by muramyl triptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma

Leonard Liebes, Christina M. Walsh, Abraham Chachoua, Ruth Oratz, David Richards, Howard Hochster, Denise Peace, Dierdre Marino, Susan Alba, Dean Le Sher, Ronald H. Blum, Jan Vilcek

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32 Scopus citations


Background: Muramyl tripeptide phos-phatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipep-tide (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. Purpose: 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-a (TNF-α), neopterin, interleukin-l-β, inter-leukin-6 (IL-6), and β2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mono-nuclear 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-a levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-a 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 β2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1β 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. Implications: 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. [J Natl Cancer Inst 84:694-699, 1992]

Original languageEnglish (US)
Pages (from-to)694-699
Number of pages6
JournalJournal of the National Cancer Institute
Issue number9
StatePublished - May 6 1992
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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