title: Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer.
abstract: Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon γ were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies.
authors: Faculty of Veterinary Medicine, Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Ghent University, Merelbeke, Belgium.
authors: L
authors: L
authors: Cicchelero
authors: Faculty of Veterinary Medicine, Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Ghent University, Merelbeke, Belgium.
authors: S
authors: S
authors: Denies
authors: Faculty of Veterinary Medicine, Department of Medical Imaging of Domestic Animals, Ghent University, Merelbeke, Belgium.
authors: H
authors: H
authors: Haers
authors: Faculty of Veterinary Medicine, Department of Medical Imaging of Domestic Animals, Ghent University, Merelbeke, Belgium.
authors: K
authors: K
authors: Vanderperren
authors: Faculty of Veterinary Medicine, Department of Medical Imaging of Domestic Animals, Ghent University, Merelbeke, Belgium.
authors: E
authors: E
authors: Stock
authors: Faculty of Veterinary Medicine, Department of Pathology, Bacteriology and Poultry Diseases, Ghent University, Merelbeke, Belgium.
authors: L
authors: L
authors: Van Brantegem
authors: Small Animal Hospital, Faculty of Veterinary Medicine, Department of Medicine and Clinical Biology of Small Animals, Ghent University, Merelbeke, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors: H
authors: H
authors: de Rooster
authors: Faculty of Veterinary Medicine, Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Ghent University, Merelbeke, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors: N N
authors: NN
authors: Sanders
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004283:Dog Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004285:Dogs; D053672:Electrochemotherapy / Q000379:methods / Q000662:veterinary*; D005260:Female; D015316:Genetic Therapy / Q000379:methods / Q000662:veterinary*; D007167:Immunotherapy / Q000379:methods / Q000662:veterinary; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000662:veterinary*; D014463:Ultrasonography / Q000662:veterinary
chemical_list: D016207:Cytokines; D018664:Interleukin-12
keywords: angiogenesis; contrast-enhanced ultrasound; electroporation; gene transfer; immune stimulation; interleukin 12; spontaneous tumours