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

Abstract

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.

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-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.

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.

• Authors: L Liebes, C M Walsh, A Chachoua, R Oratz, D Richards, H Hochster, D Peace, D Marino, S Alba, D Le Sher
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 84 Issue 9 Pg. 694-9 (May 06 1992) ISSN: 0027-8874 [Print] United States
• PMID: 1569602 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Interleukin-1
• Interleukin-6
• Phosphatidylethanolamines
• Tumor Necrosis Factor-alpha
• beta 2-Microglobulin
• mifamurtide
• Biopterin
• Acetylmuramyl-Alanyl-Isoglutamine
• Neopterin

Topics

• Acetylmuramyl-Alanyl-Isoglutamine (analogs & derivatives, therapeutic use)
• Adjuvants, Immunologic (therapeutic use)
• Biopterin (analogs & derivatives, blood)
• Cytotoxicity, Immunologic
• Drug Evaluation
• Humans
• Interleukin-1 (blood)
• Interleukin-6 (blood)
• Leukocyte Count
• Melanoma (therapy)
• Monocytes (immunology)
• Neoplasm Metastasis
• Neopterin
• Phosphatidylethanolamines (therapeutic use)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)
• beta 2-Microglobulin (metabolism)