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Gene therapy with IL12 in combination with electrochemotherapy for the treatment of melanoma; a preclinical study

 

Melanoma is one of the most aggressive type of skin cancer, with limited treatment options in advanced stages. The aim of the proposed preclinical study is to evaluate the therapeutic potential of a combined approach that integrates interleukin-12 (IL-12) gene electrotransfer and electrochemotherapy (ECT) for melanoma treatment. IL-12 is a cytokine with strong antitumor and immunomodulatory activity, as it promotes the activation of cytotoxic T lymphocytes and natural killer cells, and increases the expression of interferon-gamma. Using electroporation, we will enable local and efficient delivery of plasmid DNA encoding IL-12 into tumor cells. Thus, we will enhance local expression of the therapeutic protein while minimizing systemic side effects. As a cytotoxic treatment, we will use electrochemotherapy with bleomycin, which, in addition to ablation of tumor mass, also facilitates in situ antigen exposure, thereby amplifying the immunotherapy effect.

The study will be conducted on a murine melanoma model (B16-F10), where we will monitor the effects of the combined treatment on tumor growth, survival, immune marker expression, and systemic immune response. We expect the combination of IL-12 and ECT to show synergistic effects, demonstrated as statistically significant tumor growth delay and a higher complete response rate of combined therapy compared to monotherapies. We also anticipate increased infiltration of CD8+ T cells into the tumor microenvironment and elevated IFN-γ expression, indicating activation of antitumor immunity. Based on preliminary results, we expect the development of a memory immune response that could provide long-term protection. The results of this study will support the combination of IL-12 gene therapy and electrochemotherapy as a promising strategy for local and potentially locoregional control of melanoma, with the potential for further clinical development. Further, we will focus on optimizing dosing, timing of application, and understanding the molecular mechanisms underlying long-term immune protection.