Biologic therapy for osteosarcoma using liposome-encapsulated muramyl tripeptide

The successful treatment of metastases will have to include modalities that can overcome the obstacles presented by the heterogeneous nature of malignant neoplasms and the continuous evolution of variant cells. Macrophages activated to become tumoricidal by interaction with L-MTP-PE may be able to accomplish this. Osteosarcoma appears to be an ideal disease in which to employ L-MTP-PE as an additional adjuvant to present chemotherapy regimens. The lung is the most frequent site of metastases, and pulmonary micrometastases are considered to be present in the majority of patients at diagnosis. Approximately 40% of patients with osteosarcoma develop pulmonary metastases despite the administration of adjuvant chemotherapy. The 2-year disease-free interval has not improved over the past 10 years, despite multiple changes in adjuvant regimens. These data argue that there is a subpopulation of patients who harbor tumor cells that are relatively resistant to all chemotherapy. Unfortunately, this group of patients cannot be identified at the time of initial diagnosis. This necessitates the incorporation of new forms of therapy into the adjuvant chemotherapy protocols for all patients in the hope of eradicating the resistant cells harbored in the 40%. Based on the data summarized previously, L-MTP-PE may improve the clinical outcome of patients with osteosarcoma by activating pulmonary macrophages to destroy residual tumor cells that are not eliminated by chemotherapy. Monocytes from osteosarcoma patients can be rendered cytotoxic to tumor cells by in-vitro incubation with L-MTP-PE and following the intravenous administration of this agent. L-MTP-PE can be given safely to both adults and children with minimal side effects. The whole-body distribution of ^99mTc-labeled liposomes containing MTP-PE confirms that the agent is taken up by the lungs. Biologic activity in osteosarcoma patients is revealed by the elevations in plasma levels of several cytokines plus stimulation of monocyte-mediated cytotoxicity following L-MTP-PE infusion and by histologic changes in the pulmonary lesions. Ifosfamide therapy given in combination with L-MTP-PE does not suppress this immune response, as judged by both plasma cytokine levels and tumor histology. Finally, L-MTP-PE has been shown to be effective as a single agent against relapsed osteosarcoma. It is unlikely that the addition of other chemotherapeutic agents to the adjuvant chemotherapy protocols will alter the 65% to 70% 2-year disease-free survival rate associated with osteosarcoma. The preceding data indicate that L-MTP-PE is an active agent against this disease and deserves further investigation. Therefore, the inclusion of L- MTP-PE with chemotherapy is a reasonable alternative to consider to improve the response rate of this disease. A nationwide randomized phase III trial is now underway in patients with newly diagnosed osteosarcoma. This trial is being done in conjunction with the Children's Cancer Study Group and the Pediatric Oncology Group. Patients will be randomized to receive chemotherapy alone versus chemotherapy plus L-MTP-PE following resection of the primary tumor. The rationale for the addition of L-MTP-PE early in the course of the disease is that the majority of patients who relapse with pulmonary metastases will do so during the first year, while receiving chemotherapy. Therefore, employing chemotherapy first followed by L-MTP-PE therapy would nut make an impact on the disease-free survival. Pulmonary macrophages activated by L-MTP-PE will, it is hoped, eradicate those tumor cells not eliminated by or resistant to combination chemotherapy. It is further hoped that this in turn will translate into an improved disease-free survival rate, which has remained stagnant for more than 10 years.