AbstractTargeted delivery of macrophage activating agents is an attractive approach to treat micrometastatic disease. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a potent activator of monocytes/macrophages in humans, mice, and dogs. We have conducted clinical trials in dogs with malignant and highly metastatic spontaneous tumors. Presented are results of our trials evaluating L-MTP-PE in combination with surgery and chemotherapy in dogs with spontaneous osteosarcoma and hemangiosarcoma, particularly relevant malignancies having many similarities to human cancer. Osteosarcoma dogs received chemotherapy following surgery (cisplatin q 28 days×4). At completion of chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p<0.021). Dogs with splenic hemangiosarcoma received combination chemotherapy following surgery (doxorubicin and cyclophosphamide q 21 days×4). At the first chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p<0.03). These studies show that L-MTP-PE is an effective agent for treatment of metastasis and can be safely administered in combination with chemotherapy.