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 immunological gene therapy with IL-15 protein using alternative IL-15 cDNA with high translational efficiency. Two expression vectors carrying the murine 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 with 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 second vector produced only a marginal level of IL-15 protein. Although cell growth of both transfectants in vitro remained unchanged, inoculation of clones transfected with normal IL-15 cDNA resulted in progressive tumor growth, while clones transfected with alternative IL-15 cDNA led to the rejection 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), whereas the growth of the transfectants was retarded in anti-CD8 mAb- or anti-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 not against Meth 1 tumor cells, another type of fibrosarcoma derived from BALB/c mice. Thus, tumor therapy based on IL-15 gene transfection was effective against Meth A tumor cells, suggesting a possible application to human neoplasms.
Kimura
K
K
Research Institute for Disease Mechanism and Control, First Department of Surgery, Nagoya University School of Medicine, Japan.
Nishimura
H
H
Hirose
K
K
Matsuguchi
T
T
Nimura
Y
Y
Yoshikai
Y
Y
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014176:Protein Biosynthesis; D014162:Transfection
D019409:Interleukin-15