Modulation of Monocyte Functions by Muramyl Triptide Phosphatidylethanolamine in a Phase II Study in Patients With Metastatic Melanoma

Abstract

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 β ₂ -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 β ₂ -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]