PHARMACOKINETICS AND IMMUNOMODULATORY EFFECTS ON MONOCYTES DURING PROLONGED THERAPY WITH LIPOSOMAL MURAMYLTRIPEPTIDE

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patient s (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharm acokinetic 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. N o 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 T NFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not the reafter. In contrast, MTP-PE caused a persistent, 2-fold increase in s erum neopterin and young forms of granulocytes (bands) during week 1 t o 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyt e 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 cytoto xicity and in-vitro cytokine production was transiently enhanced in we ek 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex v ivo monocyte cytokine and tumor cytotoxic response was dependent on pr etherapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neo pterin and juvenile blood granulocytes. The long lasting biologic effe cts may be relevant to direct future clinical studies with liposomal M TP-PE in an adjuvant setting.