Non-clinical evaluation of pmIL12 gene therapy for approval of the phase I clinical study

• Published in: Scientific reports Vol. 14; no. 1; pp. 22288 - 13
• Main Authors: Markelc, Bostjan, Jesenko, Tanja, Kranjc Brezar, Simona, Omerzel, Masa, Lampreht Tratar, Ursa, Rencelj, Andrej, Matkovic, Urska, Znidar, Katarina, Kos, Spela, Levpuscek, Kristina, Pisljar, Ziva, Kesar, Ursa, Komel, Tilen, Bozic, Tim, Tuljak, Aneja, Hudej, Rosana, Peterka, Matjaz, Kamensek, Urska, Cör, Andrej, Gasljevic, Gorana, Nemec Svete, Alenka, Tozon, Natasa, Sersa, Gregor, Cemazar, Maja
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-09-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/152; 631/250/127; 631/67/1059/2325; 692/4028/67/1059; Animals; Antibiotic resistance; Antibiotics; Antitumor activity; Basal cell carcinoma; Biodistribution; Biological activity; Cancer therapies; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - immunology; Carcinoma, Basal Cell - therapy; Clinical trials; Clinical Trials, Phase I as Topic; CT26 colorectal carcinoma; Cyclin-dependent kinases; Cytokines; Cytomegalovirus; Drug development; Drug dosages; Drug resistance; Electroporation; Female; Females; Gene electrotransfer; Gene therapy; Genetic Therapy - methods; Health sciences; Humanities and Social Sciences; Humans; Immunosuppressive agents; Immunotherapy; Interleukin 12; Interleukin-12 - genetics; Kinases; Metastases; Mice; multidisciplinary; Pharmacodynamics; Pharmacokinetics; Plasmid DNA; Plasmids; Plasmids - genetics; Science; Science (multidisciplinary); Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - therapy; Toxicity; Tumors; Interleukin 12; Electroporation; CT26 colorectal carcinoma; Plasmid DNA; Gene electrotransfer
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-73314-x

Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.