Immunological, anti-angiogenic and clinical effects of intratumoral interleukin 12 electrogene therapy combined with metronomic cyclophosphamide in dogs with spontaneous cancer: A pilot study. (1st August 2017)

• Record Type: Journal Article
• Authors: Cicchelero, Laetitia; Denies, Sofie; Vanderperren, Katrien; Stock, Emmelie; Van Brantegem, Leen; de Rooster, Hilde; Sanders, Niek N.
• Is Part Of: Cancer letters. Volume 400(2017)
• Page Start: 205
• Page End: 218
• Publication Date: 2017-08-01
• Subjects: Angiogenesis -- Contrast-enhanced ultrasound -- Immune stimulation -- Gene transfer -- Interleukin 12 -- Metronomic cyclophosphamide; CBC complete blood count -- CEUS contrast-enhanced ultrasound -- CP cyclophosphamide -- DC dendritic cell -- DPBS Dulbecco's Phosphate-Buffered Solution -- EGT electrogene therapy -- GMP good manufacturing practice -- hGH human growth hormone -- IFN interferon -- IL-12 interleukin 12 -- IL-12 receptor beta 2 IL-12Rβ2 -- IP-10 Inducible Protein 10 -- IV intravenous -- LN lymph node -- MDSCs myeloid-derived suppressor cells -- MIG Monokine Induced by Gamma IFN -- NK natural killer -- NSAID non-steroidal anti-inflammatory drug -- PBMC peripheral blood mononuclear cells -- pDNA plasmid DNA -- PE peak enhancement -- ROI region of interest -- SAP serum alkaline phosphatase -- TAN tumor-associated neutrophil -- TSP-1 thrombospondin 1 -- TTP time-to-peak -- Treg regulatory T cell -- US ultrasound -- UTR untranslated region -- VEGF vascular endothelial growth factor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.09.015
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The immunological, anti-angiogenic and clinical effects of metronomic cyclophosphamide and 3 consecutive intratumoral interleukin (IL)-12 gene therapy (electrogene therapy (EGT)) treatments were evaluated in 6 dogs with spontaneous cancer. In all dogs, a decrease in peripheral leukocytes 2 days after IL-12 EGT coincided with erythema and swelling of the tumor. In the tumor, a transient increase in IL-12 levels was measured, whereas a continuous increase in interferon γ (IFNγ) and thrombospondin 1 (TSP-1) were determined in contrast to a continuous decrease in vascular endothelial growth factor (VEGF). In the serum, a transient increase in IL-12 and IL-10 levels were noted in contrast to a transient decrease in VEGF and TSP-1. The treatment resulted in a significant anti-angiogenic effect. Although all primary tumors continued to progress in time, this progression was slower than before treatment according to the contrast-enhanced ultrasound data. Besides the encouraging immunostimulatory and anti-angiogenic effects observed in all dogs we also noticed in 4 out of 6 dogs clinically relevant improvements in quality of life and weight. These results hold great promise for combinatorial strategies of IL-12 EGT and metronomic chemotherapy with conventional antitumor (immuno)therapies. Highlights: The combination of interleukin 12 and metronomic cyclophosphamide is safe and synergistic. IL-12-CP treatment induced an increased quality of life in dogs with spontaneous tumors. Despite primary tumor progression, clear anti-angiogenic effects were measured. IL-12-CP treatment induced pro-inflammatory changes in the tumor microenvironment.