IMMUNOTHERAPY OF ESTABLISHED MURINE TUMORS WITH LARGE MULTIVALENT IMMUNOGEN AND CYCLOPHOSPHAMIDE

Plasma membrane vesicles isolated from tumor cells can be incorporated onto 5-mu m diameter microspheres and antigen in this form, termed la rge multivalent immunogen (LMI), augments generation of tumor-specific cytotoxic T lymphocyte (CTL) responses in vivo. Treatment of mice wit h LMI at the time of challenge with tumor significantly reduced growth of several tumors in their syngeneic hosts. Our report describes the effects of LMI on established progressing tumors, including P815 solid tumor and two fibrosarcomas in a lung-metastasis model. Treatment of mice bearing established tumors (7 to 12 days) with LMI alone did not significantly reduce tumor growth or extend host survival, but highly synergistic effects of combined treatment with cyclophosphamide (Cy) a nd LMI were found. Cy alone reduced the size of P815 solid tumors, but within a few days, the tumors began to grow progressively, and surviv al was only marginally extended. However, Cy followed 2 to 3 days late r by a single injection of LMI resulted in prolonged reduction of tumo r growth and significant extension of survival; in some experiments, t umors became undetectable in the majority of treated mice, and the mic e survived indefinitely. Essentially the same results were obtained in experiments examining survival of mice bearing established MCA-203 fi brosarcoma. LMIs were uniquely effective in acting synergistically wit h Cy; antigen in the form of irradiated tumor cells or plasma membrane in adjuvant were ineffective, and free plasma-membrane antigen (not o n microspheres) had only marginal effects. There has been considerable interest in the possibility of using tumor antigen to enhance tumor-s pecific immune responses, and clinical trials using this approach are showing some promise. The results described here suggest that altering the form of antigen by purifying plasma membranes and incorporating t hem onto microspheres might significantly improve the efficacy of tumo r immunotherapy with antigen.