Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice
- Manuela Gonzalez-Aparicio1,
- Pilar Alzuguren1,
- Itsaso Mauleon1,
- Jose Medina-Echeverz1,
- Sandra Hervas-Stubbs1,
- Uxua Mancheno1,
- Pedro Berraondo1,
- Julien Crettaz1,
- Gloria Gonzalez-Aseguinolaza1,
- Jesus Prieto1,2,
- Ruben Hernandez-Alcoceba1
- 1Division of Gene Therapy and Hepatology, CIMA, University of Navarra, Foundation for Applied Medical Research, Av. Pio XII, Pamplona, Spain
- 2CIBERehd, University Clinic of Navarra, Pamplona, Spain
- Correspondence to Dr Ruben Hernandez-Alcoceba, RHA, Edificio CIMA, Av. Pio XII, 55, 31008-Pamplona, Navarra, Spain;
- Revised 16 July 2010
- Accepted 1 August 2010
- Published Online First 20 September 2010
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
- colorectal cancer
- adenoviral vectors
- colorectal metastases
- gene therapy
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.