Cytokine Production and Immune Cell Activation in Melanoma Patients Treated with Liposomal Muramyl Tripeptide (CGP 19835A Lipid)¹

Abstract

We conducted a pilot study using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) preoperatively in patients with stage III or IV resectable melanoma who were at high risk for recurrence. Patients received L-MTP-PE for 1 month before surgery and then 5 months postoperatively. Several immune parameters were monitored during preoperative therapy to search for correlations with clinical (tumor) response. The 18 patients were classified into three groups according to their responses and disease-free intervals: no evidence of disease (NED) at week 24 of therapy, relapse during therapy and progressive disease on therapy noted at the time of surgery. Six of nine patients in the NED group demonstrated increased monocyte tumoricidal activity (MTA) during week 1 of therapy. MTA increased in three of the six patients in the relapse group. MTA did not increase in the three patients who had progressive disease on therapy. Plasma neopterin levels were elevated by 72 h following the first L-MTP-PE dose in all 18 patients. Circulating levels of tumor necrosis factor were elevated in 15 of 16 patients tested, and IL-6 levels were elevated in all 18 patients. Melanoma cells from all three patients with progressive disease at the time of surgery proliferated well in vitro, whereas tumor cells from 10 of the 15 patients in the other two groups did not proliferate. There were no discernible differences among the three groups in the magnitude of IL-2-induced proliferation of tumor infiltrating lymphocytes. However, IL-2-activated TILs from the NED group exhibited cytotoxicity against autologous tumor cells in vitro. In summary, whereas L-MTP-PE stimulated several immunologic responses in all patients, the only two parameters that correlated with clinical status were MTA and the tumor proliferation assay. These two biologic assays could serve to distinguish potential responders from nonresponders early in the course of treatment.

Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma

“…Biological activity was consistently observed during the phase I and II trials, and included: increased monocyte tumoricidal activity and secretion of IL-1, as well as increased TNF-α, IL-6, C-reactive protein, neopterin in plasma (but no IFN-γ or IL-1) [57,59,[61][62][63][64][65]. Chronic treatment resulted in monocyte tachyphylaxis for cytokine secretion but not tumor cytotoxicity, which remained elevated [63].…”

Effects of Muramyl Peptides on Macrophages, Monokines, and Sleep

“…There have also been clinical trials against tumors in man. MTP-PE has been used against melanoma [140,141], sarcoma [142], and against osteosarcoma and other tumors [143][144][145]. Lipophilic derivatives might prove especially useful in tumor killing when directed against tumor sites in the liver, as was done with an MDP-L-alanyl-cholesterol derivative [146].…”

Liposomal Muramyl Tripeptide (CGP 19835A Lipid) Therapy for Resectable Melanoma in Patients Who Were at High Risk for Relapse: An Update

“…All therapy was given in the outpatient facility. At the discretion of the principal investigator, 19 of the postoperative 20 weeks of therapy were administered by the local physician. Other chemotherapy, radiation, or hormonal therapy were prohibited during L-MTP-PE treatment.…”