IL-18 Gene Therapy to Enhance Specific Tumor Immunity Through Activated Innate Immune Response

Hideaki Tahara

《Journal of Genetics and Molecular Biology》 13卷1期 (2002/03) Pp. 49-49

https://doi.org/10.30047/JGMB.200203.0008

並列摘要

Interleukin (IL)-18, initially termed IFN-gamma-inducing factor, induces high level of IFN-gamma secretion by natural killer (NK), T cells, B cells and cells of the monocyte lineage. Furthermore, IL- 18 plays an important role in enhancement of NK cell activity and induction of cytotoxic T lymphocytes (CTL). Systemic administration of recombinant (r) IL-18 is associated with significant in vivo antitumor effects. Although rIL-18rIL-12 combination therapy had the most significant and immediate anti-tumor effects, many mice so treated succumbed with lethal side effects. To apply the potent antitumor activity of IL-18 in the clinical situations, we have investigated the usefulness of local expression of IL- 18 at the tumor site using gene therapy strategy. We have successfully constructed retroviral and adenoviral vectors expressing the mature (bioactive) murine IL-18 and examined their immune and anti-tumor effects in murine tumor models.
Direct injection of the IL-18 recombinant adenoviral vector (Ad-IL-18)into an established MCA205 murine fibrosarcoma completely eradicated tumor in all animals with concomitant induction of protective systemic immunity. Co-administration of systemic IL-12 at low dose with peritumoral injections of Ad-IL-18 provided synergistic anti-tumor effects with peritumoral injections of Ad-IL-18 provided synergistic anti-tumor effects with out apparent side effects as we observed with systemic administration of both IL-18 and IL-12. Furthermore, more recent results suggest that the initial antitumor effect of locally expressed IL-18 is primarily mediated by NK activity, which plays a significant role in inducing subsequent specific immunity. This suggests that IL-18 could be utilized as a cancer gene therapy.