Immunotherapy with Interleukin-18 in Combination with Preoperative Chemotherapy with Ifosfamide Effectively Inhibits Postoperative Progression of Pulmonary Metastases in a Mouse Osteosarcoma Model

The effect of immunotherapy with interleukin-18 (IL-18) in combination with preoperative chemotherapy on the postoperative progression of pulmonary metastasis was examined using a spontaneous pulmonary metastasis model of mouse osteosarcoma. Mice were inoculated subcutaneously with highly metastatic murine osteosarcoma cells (LM8) and then underwent chemotherapy with ifosfamide (30 or 60 mg/kg body weight, days 14–16), immunotherapy with IL-18 (2 μg/mouse, days 18–24) or combined immunotherapy and chemotherapy. Tumors developed in mice were excised 21 days after cell inoculation when microscopic but not macroscopic pulmonary metastasis was observed in mice. Three weeks after the excision of the tumors, macroscopic pulmonary metastasis was observed on the surface of the lung. Administration of ifosfamide or IL-18 alone decreased the number of macroscopic pulmonary metastases, and combined administration of ifosfamide and IL-18 resulted in much greater inhibition of pulmonary metastasis. These results suggest that immunotherapy in combination with preoperative chemotherapy is highly effective in suppressing postoperative progression of pulmonary metastasis.