Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide

Abstract

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1 beta and IL-6 production were low in 9 patients (group L, < 15%) and high in 5 patients (group H, > 40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pre-therapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.

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

“…Most side effects of L-MTP-PE were minimal and included fever and rigors in the majority of patients, some tachycardia and nausea in approximately half the patients, as well as chills, myalgias, malaise and fatigue. Side effects decreased in intensity and frequency during the course of treatment [58,59,61]. They were believed to result directly from L-MTP-PE biological activity, particularly the secretion of As fever and chills, the major side effects following L-MTP-PE infusion, could be prevented by administration of anti-inflammatory drugs, a series of studies were conducted to determine whether COX inhibitors interfere with L-MTP-PE action.…”

“…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

“…However, administration of MTP-PE to pigs caused a desensitization to endotoxin-induced shock [157]. MTP-PE caused fever and nausea in human cancer patients, but the symptoms declined over time, suggesting desensitization [158]. MTP-PE also caused fever and nausea in healthy volunteers testing a vaccine, but the symptoms disappeared within 48 h [159].…”

Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases

“…Biological activities, including increased monocyte antitumor activity as well as cytokine secretion (IL-1, IL-6, TNF-α and C-reactive protein [CRP]) in plasma were observed during Phase I and II trials [16][17][18]47,48,50,51]. A Phase II trial using L-MTP-PE was undertaken in relapsed osteosarcoma patients to determine whether L-MTP-PE therapy could improve the progression-free interval in this high-risk group of patients.…”

“…Exploratory Phase I studies were conducted in patients with various advanced malignancies, and found 4-6 mg/m 2 to be the maximum tolerated dose and 0.5-2.0 mg/m 2 as the optimal biological activity dose [17,23,[47][48][49][50]. Biological activities, including increased monocyte antitumor activity as well as cytokine secretion (IL-1, IL-6, TNF-α and C-reactive protein [CRP]) in plasma were observed during Phase I and II trials [16][17][18]47,48,50,51].…”