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

Čemažar, Maja; Serša, Gregor; Pavlin, Darja; Tozon, Nataša

doi:10.5772/20734

Cited by 12 publications

(14 citation statements)

References 77 publications

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“…46 The therapy with human IL-12 gene therapy resulted in prolonged survival of the patients, even for more than 4 years in grade III MCT. 47 In addition, antitumour effect of intratumoural IL-12 electrogene therapy alone was already evaluated in canine mast cell tumours. 23 In the clinical study 8 dogs with 11 mast cell tumours were treated with direct intratumour application of IL-12 gene electrotransfer.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of electrochemotherapy combined with peritumoral IL‐12 gene electrotransfer of canine mast cell tumours

Čemažar

Avguštin

Pavlin

et al. 2016

Vet Comparative Oncology

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Electrochemotherapy combined with peritumoral interleukin-12 (IL-12) gene electrotransfer was used for treatment of mast cell tumours in 18 client-owned dogs. Local tumour control, recurrence rate, as well as safety of combined therapy were evaluated. One month after the therapy, no side effects were recorded and good local tumour control was observed with high complete responses rate which even increased during the observation period to 72%. IL-12 gene electrotransfer resulted in 78% of patients with detectable serum IFN-and/or IL-12 levels. In the treated tumours vascular changes as well as minimal T-lymphocytes infiltration was observed. After 1 week, the plasmid DNA was not detected intra-or peritumorally and no horizontal gene transfer was observed. In summary, our study demonstrates high antitumour efficacy of electrochemotherapy combined with IL-12 electrotransfer, which also prevented recurrences or distant metastases, as well as its safety and feasibility in treatment of canine mast cell tumours.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of electrochemotherapy combined with peritumoral IL‐12 gene electrotransfer of canine mast cell tumours

Čemažar

Avguštin

Pavlin

et al. 2016

Vet Comparative Oncology

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“…However, a major drawback of electrochemotherapy is the lack of systemic effect. With the intent of adding an efficient systemic antitumor treatment modality, adjuvant immunotherapy with different cytokines (IL-2, TNF-α, GM-CSF and IL-12) has already been explored 7–19. Among the tested cytokines, interleukin-12 (IL-12) seems a promising one, thus it deserves further investigations on its combined use with electrochemotherapy, predominantly on its proven good local and systemic antitumor effects 19,20…”

Section: Introductionmentioning

confidence: 99%

Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity

Sedlar¹,

Dolinšek²,

Markelc³

et al. 2012

Radiology and Oncology

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Background.Electrochemotherapy provides good local tumor control but requires adjuvant treatment for increased local response and action on distant metastasis. In relation to this, intramuscular interleukin-12 (IL-12) gene electro-transfer, which provides systemic shedding of IL-12, was combined with local electrochemotherapy with cisplatin. Furthermore, the dependence on tumor immunogenicity and immunocompetence of the host on combined treatment response was evaluated.Materials and methods.Sensitivity of SA-1 sarcoma and TS/A carcinoma cells to electrochemotherapy with cisplatin was tested in vitro. In vivo, intratumoral electrochemotherapy with cisplatin (day 1) was combined with a single (day 0) or multiple (days 0, 2, 4) intramuscular murine IL-12 (mIL-12) gene electrotransfer. The antitumor effectiveness of combined treatment was evaluated on immunogenic murine SA-1 sarcoma in A/J mice and moderately immunogenic murine TS/A carcinoma, in immunocompetent BALB/c and immunodeficient SCID mice.Results.Electrochemotherapy in vitro resulted in a similar IC50 values for both sarcoma and carcinoma cell lines. However, in vivo electrochemotherapy was more effective in the treatment of sarcoma, the more immunogenic of the tumors, resulting in a higher log cell kill, longer specific tumor growth delay, and also 17% tumor cures compared to carcinoma where no tumor cures were observed. Adjuvant intramuscular mIL-12 gene electrotransfer increased the log cell kill in both tumor models, potentiating the specific tumor growth delay by a factor of 1.8-2 and increasing tumor cure rate by approximately 20%. In sarcoma tumors, the potentiation of the response by intramuscular mIL-12 gene electrotransfer was dose-dependent and also resulted in a faster onset of tumor cures. Comparison of the carcinoma response to the combined treatment modality in immunocompetent and immunodeficient mice demonstrated that the immune system is needed both for increased cell kill and for attaining tumor cures.Conclusions.Based on the comparison of the antitumor effectiveness of electrochemotherapy to intratumoral cisplatin administration, we can conclude that the fraction of cells killed and the tumor cure rate are higher in immunogenic sarcoma tumor compared to moderately immunogenic carcinoma tumor. The tumor cell kill and cure rate depend on the immune response elicited by the destroyed tumor cells, which might depend on the tumor immunogenicity. The effect of adjuvant intramuscular mIL-12 gene electrotransfer is dependent on the amount of IL-12 in the system and the immune competence of the host, as demonstrated by the dose-dependent increase in the cure rate of SA-1 tumors after multiple intramuscular mIL-12 gene electrotransfer and in the differential cure rate of TS/A tumors growing in immunocompetent and immunodeficient mice.

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“…In dogs, IL-12 EGT has been investigated on a number of different induced and spontaneously occurring tumors [57,58,66,67]. In these studies, either human or feline IL-12 was used as a therapeutic gene due to the non-availability of canine IL-12 and high homology between canine and these two cytokines [68].…”

Section: Introductionmentioning

confidence: 99%

“…An additional two publications have described a slightly different approach to IL-12 EGT, i.e ., intramuscular IL-12 EGT [66,79]. Our research group performed a feasibility and safety study on electrotransfection of IL-12 plasmid into canine skeletal muscle [78].…”

Section: Introductionmentioning

confidence: 99%

“…Hematological and biochemical parameters remained within reference limits throughout the whole observation period (2 months). Based on the results of this study, intramuscular IL-12 EGT was employed in tumor-bearing dogs [66]. The study was performed on a total of six dogs, three of them with mast cell tumors grade II and III, and the remaining three with pulmonary histiocytic sarcoma, osteosarcoma and mammary adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

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IL-12 based gene therapy in veterinary medicine

et al. 2012

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The use of large animals as an experimental model for novel treatment techniques has many advantages over the use of laboratory animals, so veterinary medicine is becoming an increasingly important translational bridge between preclinical studies and human medicine. The results of preclinical studies show that gene therapy with therapeutic gene encoding interleukin-12 (IL-12) displays pronounced antitumor effects in various tumor models. A number of different studies employing this therapeutic plasmid, delivered by either viral or non-viral methods, have also been undertaken in veterinary oncology. In cats, adenoviral delivery into soft tissue sarcomas has been employed. In horses, naked plasmid DNA has been delivered by direct intratumoral injection into nodules of metastatic melanoma. In dogs, various types of tumors have been treated with either local or systemic IL-12 electrogene therapy. The results of these studies show that IL-12 based gene therapy elicits a good antitumor effect on spontaneously occurring tumors in large animals, while being safe and well tolerated by the animals. Hopefully, such results will lead to further investigation of this therapy in veterinary medicine and successful translation into human clinical trials.

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

Cited by 12 publications

References 77 publications

Efficacy and safety of electrochemotherapy combined with peritumoral IL‐12 gene electrotransfer of canine mast cell tumours

Efficacy and safety of electrochemotherapy combined with peritumoral IL‐12 gene electrotransfer of canine mast cell tumours

Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity

IL-12 based gene therapy in veterinary medicine

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