Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice

• Published in: Gut Vol. 60; no. 3; pp. 341 - 349
• Main Authors: Gonzalez-Aparicio, Manuela, Alzuguren, Pilar, Mauleon, Itsaso, Medina-Echeverz, Jose, Hervas-Stubbs, Sandra, Mancheno, Uxua, Berraondo, Pedro, Crettaz, Julien, Gonzalez-Aseguinolaza, Gloria, Prieto, Jesus, Hernandez-Alcoceba, Ruben
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.03.2011; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: 5-Fluorouracil; adenoviral vectors; adenovirus; Adenoviruses; Animal models; Animals; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer therapies; CD8 antigen; Chemotherapy; Colon cancer; Colorectal cancer; colorectal metastases; Colorectal Neoplasms - immunology; Combined Modality Therapy; Cooperation; Cytokines; Cytotoxicity; Digestive tract; Down-Regulation - drug effects; Expression vectors; Female; Gastroenterology. Liver. Pancreas. Abdomen; gemcitabine; Gene therapy; Genes; Genetic Therapy - methods; Genetic Vectors; Immune system; Immune Tolerance - drug effects; Immunoregulation; Immunostimulation; immunotherapy; Inoculation; Interleukin 12; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Irinotecan; Liver; Liver - metabolism; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Lymphocytes T; Medical sciences; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Nude; Microenvironments; mifepristone; Mifepristone - pharmacology; Organoplatinum Compounds - therapeutic use; oxaliplatin; Rodents; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Suppressor cells; Transduction, Genetic; Tumor Microenvironment - immunology; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Rectal disease; Liver; Rodentia; Colorectal cancer; Interleukin 12; Malignant tumor; Microenvironment; Metastasis; Colonic disease; Alkylating agent; Vertebrata; Mammalia; Oxaliplatin; Mouse; Animal; Gastroenterology; Digestive diseases; Intestinal disease; Cancer; Platinum II Complexes
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2010.211722

Background and aimsNew 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.ObjectiveTo 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.MethodsA 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.ResultsIntrahepatic 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.ConclusionsLong-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.