Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma

We hypothesize that adenovirus (Ad) vector-mediated delivery of the human i nterleukin-2 (IL-2) cDNA (AdIL2) or the murine IL-12 cDNA heterodimer (AdIL 12) would produce high concentrations of cytokines in the local hepatic mil ieu to induce host responses sufficient to inhibit the growth of experiment al colon carcinoma-derived hepatic metastases. Ad vectors administered intr avenously, which is a route known to deliver >90% of the vector to the hepa tic parenchyma, achieved significant levels of each cytokine locally, with minimal levels in the sera. To examine the therapeutic effect, the AdIL2 an d AdIL12 vectors were evaluated in a hepatic metastasis model that was esta blished by injecting 3 x 10(4) cells from the poorly immunogenic syngeneic C26 colon carcinoma cell line into the right lobe of the livers of BALB/c m ice. Animals received AdIL2, AdIL12, or control virus (10(8) plaque-forming units each) intravenously for 2 days after tumor implantation, and tumor g rowth was compared with naive controls. The AdNull control tumors measured 116 +/- 25 mm(2) at 2 weeks. The control virus showed no significant antitu mor effect. In marked contrast, both AdIL2 and AdIL12 vectors that were del ivered regionally had significant antitumor effects, with AdIL2-treated ani mals having an average tumor size of 16 +/- 8 mm(2); AdIL12-treated tumors measured 6 +/- 6 mm(2) (P < .01, both compared with control). Both the AdIL 2 and AdIL12 vectors provided a significant survival advantage by log-rank analysis (P < .01), but only AdIL12 translated into an increase in mean sur vival from 27 (naive control) to 37 days. To evaluate whether these antitum or effects were T-cell-mediated, splenocytes from AdIL2-treated, AdIL12-tre ated, and naive control groups were stimulated in vitro with gamma-irradiat ed C26 tumor cells for 5 days and tested for C26 tumor cell cytolysis by an in vitro cytotoxicity assay. Splenocytes from both AdIL2- and AdIL12-treat ed animals showed a dose-dependent, T-cell-mediated, specific cytolysis of CT26 cells. AdIL12 and to a lesser extent AdIL2 induced natural killer cell activity, as determined by a dose-dependent increase in lysis of the natur al killer-specific target cell YAC-1. Overall, these data suggest that regi onal Ad-mediated delivery of IL-2 and IL-12 cDNAs may be useful for local t umor control and may warrant further investigation as a potentially useful adjuvant for the treatment of hepatic micrometastasis.