title: Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice.
abstract: OBJECTIVE
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA, University of Navarra, Foundation for Applied Medical Research, Pamplona, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gonzalez-Aparicio
authors.forename: Pilar
authors.initials: P
authors.lastname: Alzuguren
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleon
authors.forename: Jose
authors.initials: J
authors.lastname: Medina-Echeverz
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: Uxua
authors.initials: U
authors.lastname: Mancheno
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.forename: Julien
authors.initials: J
authors.lastname: Crettaz
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernandez-Alcoceba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000276:immunology; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007108:Immune Tolerance / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D014161:Transduction, Genetic; D059016:Tumor Microenvironment / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018664:Interleukin-12; D015735:Mifepristone