Advances in Interleukin-12 Gene Therapy for Acquired Liver Diseases

Interleukin-12 (IL-12) is a multifunctional cytokine that stimulates both innate and adaptive immunity, acting as a key regulator of cell-mediated immune responses. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer and antiviral agent. The promising data obtained by the administration of IL-12 recombinant protein in preclinical animal models of cancer and chronic viral hepatitis raised hopes that recombinant IL-12 could be a powerful therapeutic agent against both pathologies. However, clinical trials revealed a modest clinical response that was limited by the development of an adaptive response that down-regulated IL-12 activity and by severe toxicity when high doses of this cytokine were used. Gene therapy can significantly increase cytokine expression in the target organ without excessively elevating systemic cytokine levels, which leads to an increased efficacy/toxicity ratio. Early clinical trials with short-term IL-12 expression vectors have set the proof-of-concept that local production of IL-12 inside a tumor can stimulate tumor infiltration by effector immune cells, sometimes followed by tumor regression. Recent advances in long-term expression vectors for the delivery of IL-12 or lytic viruses armed with this cytokine may be key to unlocking the therapeutic potential of IL-12. However, the new generation of IL-12 gene therapy protocols should cope with two major limitations. First, promoter silencing induced by IL-12 may abrogate long-term production of this cytokine. Second, regulatory immune systems induced by IL-12 should be blocked to maximize antitumor and antiviral activity.