OI Ljubljana

Immuno gene electrotransfer of IL-12 and IL-2 in immunologically cold/hot tumors

ARRS code: J3-2528
Title: Immuno gene electrotransfer of IL-12 and IL-2 in immunologically cold/hot tumors
Duration: 01.09.2020 – 31.08.2023
Applicant research organisation: 302 INSTITUTE OF ONCOLOGY LJUBLJANA
Poject leader: 14575 Maja Čemažar
Financing: Slovenian Research Agency


Tackling cancer is of fundamental importance for Europe’s future and is one of the priorities in the area of health of the new EU commission. Numbers suggest that cancer cases in the EU will double by 2035. Therefore, new approaches are needed that will improve cancer prevention, diagnosis, treatment and survivorship and will contribute to reducing the suffering of cancer in Europe. One of the new approaches in the field of treatment of cancer is gene therapy. First gene therapy medicines have already been approved in 2003 (recombinant human adenovirus encoding p53 – Gendicine) and 2005 (recombinant human adenovirus type 5 H101 – Oncorine), while lately, 3 new products were approved (axicabtagene ciloleucel, talimogene laherparepvec and tisagenlecleucel) from 2015 to 2018, demonstrating that gene therapy products are new, at the stage of development, that could be safely applied in the treatment. Besides great progress in the field of viral vectors, a pronounced progress has also been made in plasmid DNA development, which is assumed to be safer than viral vectors. However, since plasmid DNA alone is unable to cross the cell membrane, a delivery system, is needed to deliver the plasmid into the target cells. Electroporation as a delivery system, is currently the most clinically advanced and is used in combination with plasmid encoding interleukin-12 (IL-12) in clinical studies in US for treatment of melanoma. Another cytokine that is still used as a recombinant protein for melanoma and renal cell carcinoma treatment is interleukin 2 (IL-2), which is given at high doses and intravenously, but preclinical studies using plasmid encoding IL-2 were also performed demonstrating good tumor response. Although, current immune therapies with check point inhibitors resulted in pronounced antitumor effects in certain cancer types, there is a subset of patients who do not respond to therapy with checkpoint inhibitors and do not benefit from this therapy. In addition, also some specific cancer types do not respond to this therapy. The main reason for this is lack of or low immunogenicity of tumors, which can be denoted as immunologically cold tumors. Thus, therapies that would turn immunologically cold to tumors with so-called inflamed immune signature (immunologically hot tumors) should be developed. The motivation and rational for combining IL-12 and IL-2 cytokines are based on their modes of action; these two cytokines reciprocally upregulate each other's receptors and use separate signaling pathways to induce different but complementary biological effects. Our hypothesis is that combination of local IL-12 and IL-2 gene electrotransfer will result in pronounced antitumor effect in immunologically hot tumors. In addition, it would turn immunologically cold phenotype tumors into immunologically hot phenotype, thus offering the potential for further treatment options. The work will be divided in to 5 workpackeges aiming to evaluate and determine the best timing and dosing of the combined treatment together with elucidation of underlying mechanisms for antitumor effect. We expect that this combined treatment will result in good antitumor effectiveness in immunologically hot tumors, that it will change the phenotype of immunologically cold tumors toward immunologically hot phenotype and that it will also results in abscopal/systemic effect of the therapy. The results of the project will be published in gold open access journal and communicated to general public through social media.



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