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Projects / Programmes source: ARIS

Monitoring of the clinical and immune response to improve the outcome of combined electrochemotherapy and IL-12 gene therapy in dogs with spontaneous peripheral tumours

Research activity

Code Science Field Subfield
4.04.03  Biotechnical sciences  Veterinarian medicine  Therapy and health prevention of animals 

Code Science Field
4.03  Agricultural and Veterinary Sciences  Veterinary science 
Keywords
veterinary medicine, clinical oncology, dogs, electrochemotherapy, gene electrotransfer, IL-12
Evaluation (rules)
source: COBISS
Researchers (22)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  14575  PhD Maja Čemažar  Oncology  Researcher  2020 - 2023  1,438 
2.  21699  Aleksander Jenko    Technical associate  2020 - 2023 
3.  53480  Anja Kalin  Veterinarian medicine  Junior researcher  2020 
4.  23945  Rok Korljan    Technical associate  2020 - 2023 
5.  27733  PhD Tina Kosjek  Control and care of the environment  Researcher  2020 - 2023  363 
6.  36681  PhD Martina Krofič Zel  Veterinarian medicine  Researcher  2020 - 2023  27 
7.  36367  PhD Urša Lampreht Tratar  Oncology  Researcher  2020 - 2023  126 
8.  39087  PhD Nina Milevoj  Veterinarian medicine  Researcher  2020 - 2022  55 
9.  25587  PhD Ana Nemec  Veterinarian medicine  Researcher  2020 - 2023  337 
10.  16308  PhD Alenka Nemec Svete  Veterinarian medicine  Researcher  2020 - 2023  218 
11.  53481  PhD Matic Pavlica  Biotechnical sciences  Junior researcher  2020 - 2023 
12.  24507  PhD Darja Pavlin  Veterinarian medicine  Researcher  2020 - 2023  166 
13.  25588  PhD Tanja Plavec  Veterinarian medicine  Researcher  2022 - 2023  143 
14.  32224  Estera Pogorevc  Veterinarian medicine  Technical associate  2020 - 2023  30 
15.  18086  Katarina Ramljak    Technical associate  2020 - 2023 
16.  29350  PhD Urška Ravnik Verbič  Veterinarian medicine  Researcher  2020 - 2023  43 
17.  08800  PhD Gregor Serša  Oncology  Researcher  2020 - 2023  1,520 
18.  20493  Renata Šušnjara    Technical associate  2020 - 2023 
19.  18884  PhD Tanja Švara  Veterinarian medicine  Researcher  2020 - 2023  229 
20.  33348  PhD Katerina Tomsič  Veterinarian medicine  Researcher  2020 - 2023  45 
21.  13328  PhD Nataša Tozon  Veterinarian medicine  Head  2020 - 2023  390 
22.  54713  PhD Jurij Žel  Veterinarian medicine  Researcher  2021 - 2022  29 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0406  University of Ljubljana, Veterinary Faculty  Ljubljana  1627139  10,934 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,855 
3.  0302  Institute of Oncology Ljubljana  Ljubljana  5055733000  15,816 
Abstract
Immune therapies, based on the encouraging results of preclinical and clinical studies, have strongly influenced cancer treatment guidelines in recent years, especially in immunogenic tumours. Beyond immune-based antibodies, the development of basic cancer research is focused on DNA vaccination and therapies. Significant progress has also been made in the development of plasmid DNA. The most advanced plasmid DNA and electroporation immune therapy is interleukin-12 (IL-12) immune therapy, which is already on the priority list in the US to become an orphan drug. Plasmid DNA alone cannot cross the cell membrane, so a physically mediated transfer system, electroporation, is used to transfer the plasmid to the target cells. Electroporation is currently used for electrochemotherapy (ECT) purposes (the combination of cytotoxic drugs, such as bleomycin or cisplatin, with electroporation). The application of electrical pulses increases the permeability of the cell membrane, which allows increased uptake of the drug. Determination of bleomycin concentration in blood serum or plasma and target tumour tissue in a human clinical study suggested the possibility of a decrease in bleomycin dose in elderly patients. Electroporation can also be used for gene electrotransfer (GET) with IL-12 is one of the most advanced immune gene therapies. In preclinical and clinical studies in dogs with spontaneous tumours, it has already proven to be safe and effective. In preclinical studies in mice, the induction of long-term antitumor immunity, one of the major effects of GET with IL-12, has been demonstrated. The antitumor effect of GET IL-12 is multifaceted and includes antiangiogenic effect, activation of cytotoxic T lymphocyte activity and activation of M1 macrophages, with systemic cytokine concentration lower than recombinant cytokines or adenoviral delivery, meaning safer treatment. An important advantage of this type of treatment is the low immunogenicity of the plasmids compared to the viral vectors, which allows repeated DNA application. A clinical study treating malignant melanoma metastasis in humans has shown that intratumoural GET with IL-12 may produce a systemic "abscopal" effect on distant, untreated tumours. The combination of ECT and GET with IL-12 is already used to treat different tumours in dogs, but many questions remain regarding bleomycin dosing, the site of administration of the plasmid, and the reasons for the individually different response to therapy. The main objective of the proposed project is to optimize the components of combined therapy in order to improve treatment efficacy and reduce side effects. For this purpose, we will prepare a protocol for implementation of a clinical study, including a risk assessment in dogs with spontaneous tumours, in which we expect to determine the pharmacokinetic profile of bleomycin in dogs of different ages and body weights, and to determine a suitable time window for electroporation after cytostatic administration. We also expect to demonstrate that GET with intratumoral administration of IL-12 is equally or even more successful compared to peritumoral administration. By determining the expression of selected tumor-infiltrating lymphocytes (TLIs) (CD8 +, Treg) and programmed death receptors and ligands (PD-1/PDL-1) in tissue specimens prior to treatment, we will be able to determine the frequency and number of treatments in correlation with clinical data. Better response to treatment is expected in animals where there are fewer regulatory T lymphocytes and PD-1 positive cells in the tumour microenvironment, and in animals where IL-12 GET treatment will result in a decrease in circulating regulatory T lymphocytes and CD8 + lymphocytes. Prior to treatment, we will also analyze the composition of the intestinal microbiota and, in correlation with the success of the therapy and other biomarkers, we will prepare recommendations for regulating the intestinal microbiota.
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