Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice.
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.
Gonzalez-Aparicio
Manuela
M
Division of Gene Therapy and Hepatology, CIMA, University of Navarra, Foundation for Applied Medical Research, Pamplona, Spain.
Alzuguren
Pilar
P
Mauleon
Itsaso
I
Medina-Echeverz
Jose
J
Hervas-Stubbs
Sandra
S
Mancheno
Uxua
U
Berraondo
Pedro
P
Crettaz
Julien
J
Gonzalez-Aseguinolaza
Gloria
G
Prieto
Jesus
J
Hernandez-Alcoceba
Ruben
R
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
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018664:Interleukin-12; D015735:Mifepristone