Macrophages as effectors of tumor immunity

The continuous evolution of variant cells within heterogeneous malignant neoplasms dictates that therapy of disseminated cancer should include a modality to overcome heterogeneity. Macrophages activated to the tumoricidal state through their interaction with liposomes containing immunomodulators can accomplish this task. Tumoricidal macrophages recognize and destroy neoplastic cells in vitro and in vivo while leaving nonneoplastic cells unharmed. Moreover, macrophage destruction of tumor cells apparently is not associated with the development of appreciable tumor cell resistance. Phagocytic mononuclear cells clear intravenously administered liposomes from the circulation. When the liposomes contain immunomodulators, cytotoxic macrophages are generated. Repeated intravenous injections of liposomes containing immunomodulators have been shown to eradicate cancer metastases in several murine tumor systems and in spontaneous canine osteosarcoma. Liposomes containing MTP-PE not only activate tumoricidal properties in blood monocytes of cancer patients but also, according to the results of phase I clinical trials, are well tolerated and do not produce serious toxic side effects. In vivo macrophage-tumor interactions are regulated by such factors as the ratio of macrophages to target cells, the state of activation of the macrophages, and the rate of tumor cell proliferation. The treatment of metastases by macrophage activation therefore would be most successful when the metastases are small or slow to proliferate and are infiltrated by a large number of tumoricidal macrophages.