Electrogene therapy with interleukin-12 in canine mast cell tumors

Abstract

BackgroundMast cell tumors (MCT) are the most common malignant cutaneous tumors in dogs with extremely variable biological behaviour. Different treatment approaches can be used in canine cutaneous MCT, with surgical excision being the treatment of choice. In this study, electrogene therapy (EGT) as a new therapeutic approach to canine MCTs, was established.Materials and methods.Eight dogs with a total of eleven cutaneous MCTs were treated with intratumoral EGT using DNA plasmid encoding human interleukin-12 (IL-12). The local response to the therapy was evaluated by repeated measurements of tumor size and histological examination of treated tumors. A possible systemic response was assessed by determination of IL-12 and interferon- γ (IFN-γ) in patients’ sera. The occurence of side effects was monitored with weekly clinical examinations of treated animals and by performing basic bloodwork, consisting of the complete bloodcount and determination of selected biochemistry parameters.ResultsIntratumoral EGT with IL-12 elicits significant reduction of treated tumors’ size, ranging from 13% to 83% (median 50%) of the initial tumor volume. Additionally, a change in the histological structure of treated nodules was seen. There was a reduction in number of malignant mast cells and inflammatory cell infiltration of treated tumors. Systemic release of IL-12 in four patients was detected, without any noticeable local or systemic side effects.ConclusionsThese data suggest that intratumoral EGT with plasmid encoding IL-12 may be useful in the treatment of canine MCTs, exerting a local antitumor effect.

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…Data on kinetics of transgene release in dogs after intramuscular IL-12 EGT would be helpful for clinical application to determine the best time intervals for treatment repetitions in each individual patient in order to achieve the maximum therapeutic effect. In our study, intramuscular EGT did not exert such pronounced local antitumor effect on treated tumors compared to direct intratumoral IL-12 EGT (Chuang et al 2009;Pavlin et al, 2011). In four of our patients, where tumors were not surgically removed and the size of intact tumors could be repeatedly measured, there was no regression in tumor size after performed EGT.…”

“…In four of our patients, where tumors were not surgically removed and the size of intact tumors could be repeatedly measured, there was no regression in tumor size after performed EGT. In comparison, with intratumoral IL-12 EGT volumes of treated canine mast cell tumors reduced significantly by over 50% (Pavlin et al, 2011) and even complete remissions were achieved in experimentally induced transmissible veneral tumors in dogs (Chuang et al, 2009). This discrepancy in antitumor effectiveness of intratumoral versus intramuscular IL-12 EGT has already been shown in experimentally induced tumors in preclinical studies.…”

“…In vitro it is already routinely used as a method for intracellular delivery of a variety of molecules, e. g. RNA, DNA, dyes, ions, chemotherapeutic drugs, etc. In vivo it has shown a great potential for two prospective therapeutic approaches in oncology, electrochemotherapy and electrogene therapy (EGT), both already used in clinical practice in both human and veterinary medicine Daud et al 2008;Kodre et al, 2005;Mir et al, 1998;Pavlin et al, 2011;Reed et al, 2010;Sersa et al, 2000;Tozon et al, 2001Tozon et al, , 2005. This method of transgene delivery can be applied to almost any tissue in a living organism, with research focused primarily on tumor tissue, skin and skeletal muscle (Cemazar & Sersa, 2007).…”

“…In clinical settings, intratumoral IL-12 EGT has been successfully used both in humans (Daud et al, 2008), as well as dogs (Cutrera et al, 2008;Pavlin et al, 2011;Reed et al, 2010). In all of presently published studies in tumor-bearing dogs, EGT has been performed with intratumoral delivery of IL-12 either alone (Chuang et al, 2009;Pavlin et al, 2011), or in combination with electrochemotherapy with bleomycin (Cutrera et al, 2008;Reed et al, 2010). The only published intramuscular IL-12 EGT in dogs was performed on healthy experimental beagles (Pavlin et al, 2008), showing feasibility, efficacy and safety of this approach.…”

“…With the advances in the field of gene therapy, this new therapeutic tool is steadily gaining its acceptance also in clinical veterinary medicine. In the last decade, a number of gene therapy clinical trials have been conducted on companion animals, employing both viral and nonviral vectors and evaluating its effects primarily in oncologic, haematologic, musculoskeletal and cardiovascular diseases (Bergmann et al, 2003;Bodles-Brakhop et al, 2008;Dow et al, 2005;Draghia-Akli et al 2002;Herzog et al, 2001;Huttinger et al, 2008;Jahnke et al, 2007;Kamstock et al, 2006;Kornegay et al, 2010;Ohshima et al, 2009;Pavlin et al, 2011;Siddiqui et al, 2007;Sleeper et al, 2010;Z. Wang et al, 2007).…”