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Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice
  1. Manuela Gonzalez-Aparicio1,
  2. Pilar Alzuguren1,
  3. Itsaso Mauleon1,
  4. Jose Medina-Echeverz1,
  5. Sandra Hervas-Stubbs1,
  6. Uxua Mancheno1,
  7. Pedro Berraondo1,
  8. Julien Crettaz1,
  9. Gloria Gonzalez-Aseguinolaza1,
  10. Jesus Prieto1,2,
  11. Ruben Hernandez-Alcoceba1
  1. 1Division of Gene Therapy and Hepatology, CIMA, University of Navarra, Foundation for Applied Medical Research, Av. Pio XII, Pamplona, Spain
  2. 2CIBERehd, University Clinic of Navarra, Pamplona, Spain
  1. Correspondence to Dr Ruben Hernandez-Alcoceba, RHA, Edificio CIMA, Av. Pio XII, 55, 31008-Pamplona, Navarra, Spain; rubenh{at}


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 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.

  • Interleukin 12
  • oxaliplatin
  • colorectal cancer
  • liver
  • adenovirus
  • adenoviral vectors
  • chemotherapy
  • colorectal metastases
  • gene therapy
  • immunotherapy

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  • Funding This work was funded in part by Fundacion Ramon Areces; Fundacion MMA; grant SAF2009-11324 from the Spanish Department of Science; Fundacion Pedro Barrie de la Maza; Condesa de Fenosa; INMUNONET-SOE1/P1/E014; Instituto de Salud Carlos III and the UTE project CIMA. JM-E was supported by a fellowship from Spanish FIS. PB was supported by a Juan de la Cierva contract from Spanish MEC and a Miguel Servet contract from Spanish Instituto de Salud Carlos III. RHA was supported by a Ramon y Cajal contract from Spanish MEC. JC was in receipt of a grant from Gobierno de Navarra.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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