Successful immunogene therapy using colon cancer cells (colon 26) transfected with plasmid vector containing mature interleukin-18 cDNA and the Ig kappa leader sequence

IL-18 is a novel cytokine that induces interferon (IFN)-gamma secretion and plays an important role in antitumor immunity. In the present study, we co nstructed plasmid vectors encoding the murine mature IL-18 cDNA linked with the Ig kappa leader sequence and the pro-IL-18 cDNA to estimate the effica cy of the mature IL-18 vector and to evaluate IL-18-producing tumor cells a s a tumor vaccine. Colon 26 cells were transfected with the abovementioned vectors or with vector alone (mock). Reverse transcription-polymerase chain reaction analysis showed increased expression of murine IL-18 cDNA in both mature IL-18 and pro-IL-18 transfectants in comparison to that in mock tra nsfected cells. The ability of the culture supernatants of mature IL-18 tra nsfectants to induce IFN-gamma secretion was extremely high (40-140 pg/10(6 ) cells) in comparison to that of pro IL-18 transfectants (4-18 pg/ 10(6) c ells). When injected into syngeneic BALB/c mice, the growth of mature IL-18 transfectants, but not pro-IL-18 transfectants, was significantly less tha n that in mock transfected cells (P<.01, by ANOVA and analysis of covarianc e). In addition, injection of colon 26 or Meth -A cells into mice immunized with a mature IL-18 transfectant revealed acquired immunity. Depletion of natural killer cells did not affect the growth of transfectants. However, t he growth inhibitory effects were partially abrogated following treatment w ith anti-CD4(+) and anti-CD8(+) antibodies. These data suggest that the rej ection of mature IL-18/colon 26 cells was mediated through T-cell activatio n. Gene therapy using mature IL-18 transfectants containing a plasmid vecto r and the Ig<kappa> leader sequence may be a useful tumor vaccine.