Berraondo Pedro, Prieto Jesús, Gonzalez-Aseguinolaza Gloria
Division of Hepatology and Gene Therapy, Center for Investigation in Applied Medicine (CIMA), University of Navarra, 31008 Pamplona, Spain.
Curr Gene Ther. 2009 Apr;9(2):62-71. doi: 10.2174/156652309787909553.
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.
白细胞介素-12（IL-12）是一种多功能细胞因子，可刺激先天性免疫和适应性免疫，是细胞介导免疫反应的关键调节因子。IL-12的免疫调节和抗血管生成功能为将这种细胞因子用作抗癌和抗病毒药物提供了理论依据。在癌症和慢性病毒性肝炎的临床前动物模型中给予IL-12重组蛋白所获得的有前景的数据，让人们希望重组IL-12可能成为对抗这两种疾病的强大治疗剂。然而，临床试验显示临床反应有限，这受到下调IL-12活性的适应性反应的发展以及使用高剂量这种细胞因子时出现的严重毒性的限制。基因治疗可以显著增加靶器官中的细胞因子表达，而不会过度提高全身细胞因子水平，从而提高疗效/毒性比。使用短期IL-12表达载体的早期临床试验已经证明，肿瘤内部局部产生IL-12可以刺激效应免疫细胞浸润肿瘤，有时随后会出现肿瘤消退。用于递送IL-12的长期表达载体或携带这种细胞因子的裂解病毒的最新进展可能是释放IL-12治疗潜力的关键。然而，新一代IL-12基因治疗方案应应对两个主要限制。首先，IL-12诱导的启动子沉默可能会消除这种细胞因子的长期产生。其次，应由IL-12诱导的调节性免疫系统应被阻断，以最大限度地提高抗肿瘤和抗病毒活性。
