We have demonstrated that monocytes from osteosarcoma patients can be rendered tumor cytotoxic by both in vitro incubation with liposomal MTP-PE and i.v. administration of this agent. Chemotherapy did not interfere with this activation process. We have further demonstrated in phase I and phase II trials that liposomal MTP-PE can be given safely i.v. to both adults and children with minimal side effects. The findings of peripheral fibrosis with neovascularization and infiltration of the tumor with chronic inflammatory cells after liposomal MTP-PE therapy are unlike any observed following chemotherapy or surgery. Subsequent to chemotherapy, osteosarcoma lung metastases usually exhibit a zone of central necrosis, with viable tumor cells growing at the periphery of the lesion. However, in our patients following liposomal MTP-PE viable tumor cells were observed in the center of the lesion, with necrosis and fibrosis at the periphery. These changes were thus interpreted as a specific response to liposomal MTP-PE. The peripheral fibrosis observed in these tumors is reminiscent of the appearance of pulmonary tuberculosis lesions. Initially, the lesion is walled off and slow necrosis proceeds from the outside so that the lesion is replaced by fibrous tissue. Eradication of tuberculosis by chronic inflammation is a slow process. Viable bacilli can persist for months. Thus, our choice of a 3-month treatment course may have been insufficient. We have now extended our protocol to allow 6 months of therapy. Osteosarcoma appears to be an ideal disease in which to employ liposomal MTP-PE as an additional adjuvant to present chemotherapy regimens.(ABSTRACT TRUNCATED AT 250 WORDS)