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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Terapia génica del cáncer > DA - CIMA - Terapia génica y Hepatología - Terapia génica del cáncer - Artículos de revista >

Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice
Authors: Gonzalez-Aparicio, M. (Manuela)
Alzuguren, P. (Pilar)
Mauleon, I. (Itsaso)
Medina-Echeverz, J. (José)
Hervas-Stubbs, S. (Sandra)
Mancheño, U. (Uxua)
Berraondo, P. (Pedro)
Crettaz, J. (Julien)
Gonzalez-Aseguinolaza, G. (Gloria)
Prieto, J. (Jesús)
Hernandez-Alcoceba, R. (Rubén)
Keywords: Materias Investigacion::Ciencias de la Salud::Oncología
Técnica
Metástasis
Issue Date: 2011
Publisher version: http://gut.bmj.com/content/60/3/341.abstract
ISSN: 0017-5749
Citation: Gonzalez-Aparicio, M; Alzuguren, P; Mauleon, I; Medina-Echeverz, J; Hervas-Stubbs, S. "Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice". GUT 2011; 60: 341-349
Abstract
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.
Permanent link: http://hdl.handle.net/10171/17299
Appears in Collections:DA - CIMA - Terapia génica y Hepatología - Terapia génica hepatitis virales - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Terapia génica del cáncer - Artículos de revista

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