Therapy of disseminated melanoma by liposome-activated macrophages.

The uncontrolled growth of metastases is a major cause of death from melanoma. Metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. Macrophages are activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators recognize and destroy neoplastic cells in vitro and in vivo while leaving nonneoplastic cells unharmed. The mechanism(s) by which macrophages discriminate between tumorigenic and normal cells is independent of tumor cell characteristics such as immunogenicity, metastatic potential, and sensitivity to cytotoxic drugs. Moreover, macrophage destruction of tumor cells apparently is not associated with the development of tumor cell resistance. Intravenously administered liposomes are cleared from the circulation by phagocytic cells. The administration of such liposomes has been shown to activate macrophages in situ and to bring about eradication of cancer metastases in several experimental tumor systems and in dogs with spontaneous osteogenic sarcoma. Macrophage destruction of metastases in vivo is significant, provided that the tumor burden at the start of treatment is minimal. For this reason, we have been investigating various methods to achieve maximal cytoreduction in metastases by modalities such as chemotherapy or radiotherapy prior to systemic activation of macrophages. Macrophage-directed therapy has been studied in several human protocols, yielding important biological information about the safe use of liposome-encapsulated macrophage activators in cancer patients.