EFFECTIVE ANTIMETASTATIC MELANOMA VACCINATION WITH TUMOR-CELLS TRANSFECTED WITH MHC GENES AND OR INFECTED WITH NEWCASTLE-DISEASE VIRUS (NDV)/

The therapeutic efficacy of active immunization with B16-F10.9 melanom a cells transfected with syngeneic major histocompatibility complex (M HC) class-I genes, modified by infection with Newcastle Disease virus (NDV) or modified by both treatments, was compared. B16-F10.9 tumor-be aring mice were treated at various stages of tumor growth and metastas is with irradiated, modified tumor-cell vaccines. Irradiated tumor cel ls and H-2D(b) transfectants did not stimulate anti-tumor immunity whi le H-2K(b) transfectants and NDV-modified F10.9 cells showing low and high expression of MHC class-I genes efficiently prevented metastasis of small established tumors. NDV-modified parental-cell vaccines funct ioned optimally and improved overall survival by about 60%, also at ea rly stages of metastasis establishment. A synergistic effect of H-2K(b ) expression and virus modification on rejection of micrometastases wa s observed in mice bearing advanced tumors. Postoperative vaccination of mice carrying multiple metastases with NDV-modified vaccines caused significant, but incomplete, reduction of metastatic tumor load. The therapeutic effect of NDV-modified tumor vaccines was dependent on mul tiple immune mechanisms. Depletion of CD8, CD4 or NK cells by in vivo treatment with monoclonal antibodies reversed the immunotherapeutic ef fects of the vaccine. Thus, tumor xenogenization and gene modification may act synergistically to vaccinate against advanced tumors, while s ingle modalities can effectively vaccinate against metastasis at early stages of tumor growth. (C) 1994 Wiley-Liss, Inc.