Complete regression of established murine hepatocellular carcinoma by in vivo tumor necrosis factor alpha gene transfer.

BACKGROUND & AIMS: Although tumor necrosis factor (TNF)-alpha possesses a potent antitumor activity, systemic administration of TNF-alpha causes severe side effects. To circumvent this, the efficacy of tumor cell-targeted TNF-alpha gene therapy was investigated.

METHODS

Murine hepatocellular carcinoma (HCC) cells were infected with MNSM-Alb e/p-TNF-alpha retroviruses carrying the murine TNF-alpha gene under the transcriptional control of the murine albumin gene promoter, and antitumor effects induced by TNF-alpha gene transfer were examined in vitro and in vivo.

RESULTS

Although MNSM-Alb e/p-TNF-alpha retrovirally infected HCC cells showed the same in vitro cell growth as parental HCC cells, they lost their tumorigenicity when implanted in syngeneic mice and induced tumor immunity against parental HCCs. The retrovirally infected HCC cells also significantly inhibited the tumorigenicity of previously implanted parental HCCs. Furthermore, intratumoral administration of MNSM-Alb e/p-TNF-alpha retroviruses showed the antitumor effect against established HCCs, resulting in significantly prolonged survival periods. Most importantly, intratumoral implantation of MNSM-Alb e/p-TNF-alpha retroviral-producing cells completely abrogated established HCCs in mice.

CONCLUSIONS

These results indicate the potential efficacy of transferring the TNF-alpha gene via retroviral vectors directly into tumors for gene therapy against HCCs.