Division of Gene Therapy and Hepatology, CIMA, University of Navarra, Foundation for Applied Medical Research, Pamplona, Spain.
Gut. 2011 Mar;60(3):341-9. doi: 10.1136/gut.2010.211722. Epub 2010 Sep 20.
New options are needed for the management and prevention of colorectal cancer liver metastases. Interleukin 12 (IL-12) is an immunostimulatory cytokine with proven antitumour effect in animal models. Despite evidence indicating its biological effect in humans, neither the recombinant protein nor gene therapy vectors expressing IL-12 have shown a relevant benefit in patients with cancer.
To develop a new approach to overcome the difficulties in obtaining a suitable expression pattern and the immunosuppressive milieu in the tumours which contribute to this poor performance.
A high-capacity ('gutless') adenoviral vector carrying a liver-specific, mifepristone (Mif)-inducible system for the expression of IL-12 (HC-Ad/RUmIL-12) was used in combination with chemotherapy. Tumours were established in the liver of C57BL/6 mice by inoculation of MC38 colon cancer cells.
Intrahepatic injection of HC-Ad/RUmIL-12 and tailored induction regimens allowed the maintenance of safe and efficient levels of IL-12 in vivo. An individualised, stepwise increase in the dose of Mif (125-4000 μg/kg) was needed to compensate for the progressive but transient downregulation of the inducible system. Repeated cycles of Mif induction (every 24 h for 10 days) were needed for optimal tumour eradication. However, complete protection against tumour rechallenge was seen in < 25% of the animals. The administration of oxaliplatin (5 mg/kg intraperitoneally) 3 days before starting the induction regimen achieved efficient elimination of liver metastases with a single cycle of IL-12 induction, and improved protection against tumour rechallenge. This was associated with a shift in the tumour microenvironment towards a more pro-immunogenic phenotype, with an increase in the CD8+/T regulatory cell ratio and a reduction in myeloid-derived suppressor cells. These effects were not seen with 5-fluorouracil, irinotecan or gemcitabine.
Long-term controlled expression of IL-12 using an HC-Ad vector in combination with oxaliplatin is effective and clinically applicable against hepatic colon cancer metastases.
需要新的方法来管理和预防结直肠癌肝转移。白细胞介素 12（IL-12）是一种免疫刺激细胞因子，在动物模型中已证实具有抗肿瘤作用。尽管有证据表明其在人类中的生物学效应，但重组蛋白或表达 IL-12 的基因治疗载体在癌症患者中均未显示出相关益处。
开发一种新方法来克服获得合适表达模式和肿瘤中免疫抑制环境的困难，这些因素导致了这种不良表现。
使用携带肝特异性、米非司酮（Mif）诱导系统的高容量（“无肠”）腺病毒载体（HC-Ad/RUmIL-12）与化疗联合使用。通过接种 MC38 结肠癌细胞在 C57BL/6 小鼠的肝脏中建立肿瘤。
肝内注射 HC-Ad/RUmIL-12 和定制的诱导方案允许在体内维持安全有效的 IL-12 水平。需要个体化、逐步增加 Mif 的剂量（125-4000 μg/kg）来补偿诱导系统的渐进但短暂的下调。需要重复的 Mif 诱导循环（每 24 小时一次，共 10 天）以实现最佳肿瘤消除。然而，在<25%的动物中看到了对肿瘤再挑战的完全保护。在开始诱导方案前 3 天腹腔内给予奥沙利铂（5mg/kg）可通过单次 IL-12 诱导循环有效消除肝转移，并提高对肿瘤再挑战的保护。这与肿瘤微环境向更具免疫原性表型的转变相关，CD8+/T 调节细胞的比例增加，髓源抑制细胞减少。这些作用在使用 5-氟尿嘧啶、伊立替康或吉西他滨时没有看到。
使用 HC-Ad 载体联合奥沙利铂长期控制 IL-12 的表达是有效且适用于临床的，可用于治疗结直肠癌肝转移。
