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Enhancing the Efficacy of a Weak Allogeneic Melanoma Vaccine by Viral Fusogenic Membrane Glycoprotein-mediated Tumor Cell-Tumor Cell Fusion¹

Molecular Medicine Program [E. L., A. B., V. P., A. A., M. G., K. O., R. V.] and Department of Immunology [R. K.], Mayo Clinic, Rochester, Minnesota 55905; Imperial Cancer Research Fund Oncology Unit, St. James Hospital, Leeds, United Kingdom [F. E., A. M.]; and Chester Beatty Laboratories, Fulham Road, London, United Kingdom [K. J. H.]

We have investigated how to make K1735 cells, a poor allogeneic melanoma vaccine, more effective for protection against B16 in vivo. To promote antigen release in an immunologically effective manner, tumor cells were transfected with a viral fusogenic membrane glycoprotein (vesicular stomatitis virus G glycoprotein), which kills cells through the formation, and degeneration, of large multinucleated syncytia. Vaccines consisting of a 1:1 mix of fusing allogeneic and autologous cells led to dramatic increases in survival of mice in both prophylactic and therapy models, dependent upon T cells, the mechanism of tumor-tumor cell fusion, and the nature of the fusion partner. Syncytia activate macrophages and fusogenic membrane glycoprotein-mediated cell killing very efficiently promotes cross-priming of immature dendritic cells with a model tumor antigen. Our data suggest that the unique manner in which syncytia develop and die provides a highly effective pathway for tumor antigen release and presentation to the immune system and offers a novel mechanism by which cancer cell vaccines may be prepared for clinical use.

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