CLINICAL-APPLICATION OF PHOSPHOLIPID LIPOSOMES CONTAINING MACROPHAGE ACTIVATORS FOR THERAPY OF CANCER METASTASIS

The primary function of macrophages is to discriminate between 'self' and 'altered self' and to recognize and dispose of effete cells, cellu lar debris, and foreign invaders. Systemic activation of macrophages c an be accomplished by intravenous administration of phospholipid lipos omes containing natural or synthetic immunomodulators. Activated macro phages can eradicate cancer metastases in mice and spontaneous metasta ses in dogs with osteogenic sarcoma. Pharmaceutical-grade, freeze-drie d phospholipid liposomes consisting of phosphatidylcholine and phospha tidylserine (7:3 molar ratio) and containing muramyl tripeptide phosph atidylethanolamine (MTP-PE) have been studied in a multicenter Phase I trial and found to be safe. The optimal biological dose in humans was 0.5-2.0 mg/m(2), whereas the maximal tolerated dose was 6.0 mg/m(2) A Phase II trial using this commercial preparation of liposomes was rec ently completed in patients with recurrent osteosarcoma, who have a sh ort disease-free interval following surgery. In patients receiving 24 weeks of liposome-MTP-PE therapy, time to relapse was significantly pr olonged. In some patients who relapsed within 6 weeks of therapy compl etion, lung lesions were excised. The lesions were surrounded by a fib rous capsule with inflammatory macrophage infiltration. Neovasculariza tion in the peripheral fibrosis was also noted. Collectively, the data demonstrate that therapy of drug-resistant tumor cells in humans can be accomplished by the systemic activation of macrophages with phospho lipid liposomes containing the synthetic macrophage-activating agent l ipophilic MTP-PE.