Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration.
We introduced the interleukin-12 (IL-12) gene into mouse renal cell carcinoma (RenCa) cells to develop a tumor vaccine and to examine mechanisms of tumor rejection. IL-12-secreting RenCa (RenCa/IL-12) cells were completely rejected when implanted into syngeneic BALB/c but not athymic nude mice, suggesting that T cells were involved in this antitumor effect. Depletion of natural killer (NK) cells in nude mice did not affect the tumor growth of RenCa/IL-12. The simultaneous injection of mitomycin C-treated RenCa/IL-12 inhibited the tumor growth of parental RenCa injected at a distant site, whereas injection of mitomycin C-treated parental RenCa did not. The antitumor effect of RenCa/IL-12 as a cancer vaccine was induced by CD8+ T cells and NK cells and was inhibited by CD4+ T cells. Although the systemic administration of recombinant IL-18 (rIL-18) alone did not inhibit the tumor growth, it did enhance the cancer vaccine effect of RenCa/IL-12. The combination therapy of RenCa/IL-12 and the systemic administration of rIL-18 retarded even the growth of established tumors. The effector cells of this combination therapy consist not only of CD8+ T cells and NK cells but also of CD4+ T cells. This synergistic cancer vaccine effect of in situ secretion of IL-12 and the systemic administration of rIL-18 may be attributed to a functional change of CD4+ T cells.
Hara
I
I
Department of Urology, Kobe University School of Medicine, Japan.
Nagai
H
H
Miyake
H
H
Yamanaka
K
K
Hara
S
S
Micallef
M J
MJ
Kurimoto
M
M
Gohji
K
K
Arakawa
S
S
Ichihashi
M
M
Kamidono
S
S
D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D004357:Drug Synergism; D005260:Female; D016233:Immunotherapy, Active; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D020382:Interleukin-18; D018664:Interleukin-12