Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice
Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice
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DOI：
10.1136/gut.2010.211722
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发表时间：
2011-03-01
期刊：
影响因子：
24.5
通讯作者：
Hernandez-Alcoceba, Ruben
中科院分区：
文献类型：
--
作者：
Gonzalez-Aparicio, Manuela;Alzuguren, Pilar;Hernandez-Alcoceba, Ruben
背景和目的：需要新的选择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，在动物模型中具有抗肿瘤作用。尽管有证据表明它对人类有生物学效应，目的建立一种新的方法来克服获得合适的表达模式和肿瘤中免疫抑制环境的困难，这是导致这种不良表现的原因。携带用于表达IL-12的肝特异性米非司酮（Mif）诱导系统的（“无肠”）腺病毒载体（HC-Ad/RUmIL-12）与化疗联合使用。结果HC-Ad/RUmIL-12经肝内注射后，可在体内维持安全、有效的IL-12水平。需要个体化、逐步增加Mif剂量（125-4000 mg/kg），以补偿诱导系统的进行性但短暂的下调。需要重复的Mif诱导周期（每24小时，持续10天）以实现最佳肿瘤根除。然而，在小鼠中观察到对肿瘤再激发的完全保护作用。
Background and aims 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.Objective 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.Methods 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.Results 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 mg/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