Immunogene therapy of murine fibrosarcoma using IL-15 gene with high translation efficiency

We have recently found that translational efficiency is up-regulated by an alternative exon in IL-15 mRNA in mice. In a malignancy model using BALB/c mice and syngeneic Meth A fibrosarcoma (Meth A), we successfully applied im munological gene therapy with IL-15 protein using alternative IL-15 cDNA wi th high translational efficiency. Two expression vectors carrying the murin e IL-15 gene were constructed for use in tumor immunotherapy, one utilizing IL-15 cDNA with alternative exon 5 and the second utilizing IL-15 cDNA wit h normal exon 5. The first vector induced the production of a large amount of IL-15 protein in Meth A cells, whereas tumor cells transfected by the se cond vector produced only a marginal level of IL-15 protein. Although cell growth of both transfectants in vitro remained unchanged, inoculation of cl ones transfected with normal IL-15 cDNA resulted in progressive tumor growt h, while clones transfected with alternative IL-15 cDNA led to the rejectio n of the tumor. The clone producing high levels of IL-15 grew progressively in nude mice and mice treated with anti-CD4 monoclonal antibodies (mAb), w hereas the growth of the transfectants was retarded in anti-CD8 mAb- or ant i-asialo GM1 antibody-treated mice. Cured mice were shown to have generated immunity against a subsequent challenge with the wild type of Meth A but n ot against Meth 1 tumor cells, another type of fibrosarcoma derived from BA LB/c mice. Thus, tumor therapy based on IL-15 gene transfection was effecti ve against Meth A tumor cells, suggesting a possible application to human n eoplasms.