{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:23:10Z","timestamp":1789669390533,"version":"4.0.1"},"reference-count":36,"publisher":"Walter de Gruyter GmbH","issue":"3","license":[{"start":{"date-parts":[[2022,8,14]],"date-time":"2022-08-14T00:00:00Z","timestamp":1660435200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_raon-2022-0021_s_007\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune therapies are currently under intensive investigation providing in many cases excellent responses in different tumors. Other possible approach for immunotherapy is a targeted intratumoral delivery of interleukin 12 (IL-12), a cytokine with anti-tumor effectiveness. Due to its immunomodulatory action, it can be used as an imunostimulating component to in situ vaccinating effect of local ablative therapies. We have developed a phIL12 plasmid devoid of antibiotic resistance marker with a transgene for human IL-12 p70 protein. The plasmid can be delivered intratumorally by gene electrotransfer (GET).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_raon-2022-0021_s_008\">\n                    <jats:title>Patients and methods<\/jats:title>\n                    <jats:p>Here we present a first-in-human clinical trial protocol for phIL12 GET (ISRCTN15479959, ClinicalTrials NCT05077033). The study is aimed at evaluating the safety and tolerability of phIL12 GET in treatment of basal cell carcinomas in patients with operable tumors in the head and neck region. The study is designed as an exploratory, dose escalating study with the aim to determine the safety and tolerability of the treatment and to identify the dose of plasmid phIL12 that is safe and elicits its biological activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_raon-2022-0021_s_009\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The results of this trail protocol will therefore provide the basis for the use of phIL12 GET as an adjuvant treatment to local ablative therapies, to potentially increase their local and elicit a systemic response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2478\/raon-2022-0021","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T03:55:14Z","timestamp":1652154914000},"page":"398-408","source":"Crossref","is-referenced-by-count":28,"title":["Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: a first-in-human clinical trial protocol"],"prefix":"10.2478","volume":"56","author":[{"given":"Ales","family":"Groselj","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masa","family":"Bosnjak","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Jesenko","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"},{"name":"Department of Experimental Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Cemazar","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Health Sciences, University of Primorska , Izola , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bostjan","family":"Markelc","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Health Sciences, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Primoz","family":"Strojan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"},{"name":"Department of Radiation Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Sersa","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute of Oncology Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Health Sciences, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2022,8,14]]},"reference":[{"key":"2026071212035018731_j_raon-2022-0021_ref_001","doi-asserted-by":"crossref","unstructured":"Fares CM, van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 2019; 39: 147-64. doi: 10.1200\/EDBK_240837","DOI":"10.1200\/EDBK_240837"},{"key":"2026071212035018731_j_raon-2022-0021_ref_002","doi-asserted-by":"crossref","unstructured":"Nguyen KG, Vrabel MR, Mantooth SM, Hopkins JJ, Wagner ES, Gabaldon TA, et al. Localized interleukin-12 for cancer immunotherapy. Front Immunol 2020; 11: 575597. doi: 10.3389\/fimmu.2020.575597","DOI":"10.3389\/fimmu.2020.575597"},{"key":"2026071212035018731_j_raon-2022-0021_ref_003","doi-asserted-by":"crossref","unstructured":"Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, et al. Effects of single-dose interleukin-12 exposure on interleukin-12\u2013associated toxicity and interferon-\u03b3 production. Blood 1997; 90: 2541-8. doi: 10.3389\/fimmu.2020.575597","DOI":"10.3389\/fimmu.2020.575597"},{"key":"2026071212035018731_j_raon-2022-0021_ref_004","doi-asserted-by":"crossref","unstructured":"Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, et al. Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 2008; 26: 5896-903. doi:10.1200\/JCO.2007.15.6794","DOI":"10.1200\/JCO.2007.15.6794"},{"key":"2026071212035018731_j_raon-2022-0021_ref_005","doi-asserted-by":"crossref","unstructured":"Spanggaard I, Snoj M, Cavalcanti A, Bouquet C, Sersa G, Robert C, et al. Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase i first-in-man study. Hum Gene Ther Clin Dev 2013; 24: 99-107. doi: 10.1089\/humc.2012.240","DOI":"10.1089\/humc.2012.240"},{"key":"2026071212035018731_j_raon-2022-0021_ref_006","doi-asserted-by":"crossref","unstructured":"Yarmush ML, Golberg A, Ser\u0161a G, Kotnik T, Miklav\u010di\u010d D. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng 2014; 16: 295-320. doi: 10.1146\/ANNUREV-BIOENG-071813-104622","DOI":"10.1146\/annurev-bioeng-071813-104622"},{"key":"2026071212035018731_j_raon-2022-0021_ref_007","doi-asserted-by":"crossref","unstructured":"Rosazza C, Haberl Meglic S, Zumbusch A, Rols M-P, Miklavcic D. Gene electrotransfer: a mechanistic perspective. Curr Gene Ther 2016; 16: 98-129. doi: 0.2174\/1566523216666160331130040","DOI":"10.2174\/1566523216666160331130040"},{"key":"2026071212035018731_j_raon-2022-0021_ref_008","doi-asserted-by":"crossref","unstructured":"Canton DA, Shirley S, Wright J, Connolly R, Burkart C, Mukhopadhyay A, et al. Melanoma treatment with intratumoral electroporation of tavokinogene telseplasmid (pIL-12, tavokinogene telseplasmid). Immunother 2017; 9: 1309-21. doi: 10.2217\/imt-2017-0096","DOI":"10.2217\/imt-2017-0096"},{"key":"2026071212035018731_j_raon-2022-0021_ref_009","doi-asserted-by":"crossref","unstructured":"Bhatia S, Longino N V., Miller NJ, Kulikauskas R, Iyer JG, Ibrani D, et al. Intratumoral delivery of plasmid IL12 via electroporation leads to regression of injected and noninjected tumors in Merkel cell carcinoma. Clin Cancer Res 2020; 26: 598-607. doi: 10.1158\/1078-0432.CCR-19-0972","DOI":"10.1158\/1078-0432.CCR-19-0972"},{"key":"2026071212035018731_j_raon-2022-0021_ref_010","doi-asserted-by":"crossref","unstructured":"Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12. Curr Gene Ther 2010; 10: 300-11. doi: 10.2174\/156652310791823425","DOI":"10.2174\/156652310791823425"},{"key":"2026071212035018731_j_raon-2022-0021_ref_011","doi-asserted-by":"crossref","unstructured":"Telli ML, Nagata H, Wapnir I, Acharya CR, Zablotsky K, Fox BA, et al. Intratumoral plasmid IL12 expands CD8 + T cells and induces a CXCR3 gene signature in triple-negative breast tumors that sensitizes patients to anti-PD-1 therapy. Clin Cancer Res 2021; 27: 2481-93. doi: 10.1158\/1078-0432.CCR-20-3944","DOI":"10.1158\/1078-0432.CCR-20-3944"},{"key":"2026071212035018731_j_raon-2022-0021_ref_012","doi-asserted-by":"crossref","unstructured":"Greaney SK, Algazi AP, Tsai KK, Takamura KT, Chen L, Twitty CG, et al. Intratumoral plasmid IL12 electroporation therapy in patients with advanced melanoma induces systemic and intratumoral T-cell responses. Cancer Immunol Res 2020; 8: 246-54. doi: 10.1158\/2326-6066.CIR-19-0359","DOI":"10.1158\/2326-6066.CIR-19-0359"},{"key":"2026071212035018731_j_raon-2022-0021_ref_013","doi-asserted-by":"crossref","unstructured":"Algazi AP, Twitty CG, Tsai KK, Le M, Pierce R, Browning E, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. Clin Cancer Res 2020; 26: 2827-37. doi: 10.1158\/1078-0432.CCR-19-2217","DOI":"10.1158\/1078-0432.CCR-19-2217"},{"key":"2026071212035018731_j_raon-2022-0021_ref_014","doi-asserted-by":"crossref","unstructured":"Dollin Y, Rubin J, Carvajal RD, Rached H, Nitzkorski JR. Pembrolizumab and tavokinogene telseplasmid electroporation in metastatic melanoma. Int J Surg Case Rep 2020; 77: 591-4. doi: 10.1016\/J.IJSCR.2020.11.063","DOI":"10.1016\/j.ijscr.2020.11.063"},{"key":"2026071212035018731_j_raon-2022-0021_ref_015","doi-asserted-by":"crossref","unstructured":"Kos S, Bosnjak M, Jesenko T, Markelc B, Kamensek U, Znidar K, et al. Non-clinical in vitro evaluation of antibiotic resistance gene-free plasmids encoding human or murine IL-12 intended for first-in-human clinical study. Pharmaceutics 2021; 13: 1739. doi: 10.3390\/PHARMACEUTICS13101739","DOI":"10.3390\/pharmaceutics13101739"},{"key":"2026071212035018731_j_raon-2022-0021_ref_016","doi-asserted-by":"crossref","unstructured":"Kamensek U, Tesic N, Sersa G, Cemazar M. Clinically usable interleukin 12 plasmid without an antibiotic resistance gene: functionality and toxicity study in murine melanoma model. Cancers 2018; 10: 60. doi: 10.3390\/cancers10030060","DOI":"10.3390\/cancers10030060"},{"key":"2026071212035018731_j_raon-2022-0021_ref_017","doi-asserted-by":"crossref","unstructured":"Clover AJP, Salwa SP, Bourke MG, McKiernan J, Forde PF, O\u2019Sullivan ST, et al. Electrochemotherapy for the treatment of primary basal cell carcinoma; A randomised control trial comparing electrochemotherapy and surgery with five year follow up. Eur J Surg Oncol 2020; 46: 847-54. doi: 10.1016\/J.EJSO.2019.11.509","DOI":"10.1016\/j.ejso.2019.11.509"},{"key":"2026071212035018731_j_raon-2022-0021_ref_018","doi-asserted-by":"crossref","unstructured":"Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Kaatz M, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol 2021; 22: 848-57. doi: 10.1016\/S1470-2045(21)00126-1","DOI":"10.1016\/S1470-2045(21)00126-1"},{"key":"2026071212035018731_j_raon-2022-0021_ref_019","doi-asserted-by":"crossref","unstructured":"Jayaraman SS, Rayhan DJ, Hazany S, Kolodney MS. Mutational landscape of basal cell carcinomas by whole-exome sequencing. J Invest Dermatol 2014; 134: 213.20. doi: 10.1038\/JID.2013.276","DOI":"10.1038\/jid.2013.276"},{"key":"2026071212035018731_j_raon-2022-0021_ref_020","doi-asserted-by":"crossref","unstructured":"Clover AJP, de Terlizzi F, Bertino G, Curatolo P, Odili J, Campana LG, et al. Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019). Eur J Cancer 2020; 138: 30-40. doi: 10.1016\/J.EJCA.2020.06.020","DOI":"10.1016\/j.ejca.2020.06.020"},{"key":"2026071212035018731_j_raon-2022-0021_ref_021","doi-asserted-by":"crossref","unstructured":"Bertino G, Sersa G, De Terlizzi F, Occhini A, Plaschke CC, Groselj A, et al. European research on electrochemotherapy in head and neck cancer (EURECA) project: results of the treatment of skin cancer. Eur J Cancer 2016; 63: 41-52. doi: 10.1016\/J.EJCA.2016.05.001","DOI":"10.1016\/j.ejca.2016.05.001"},{"key":"2026071212035018731_j_raon-2022-0021_ref_022","doi-asserted-by":"crossref","unstructured":"Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-8. doi: 10.1126\/SCIENCE.AAA1348","DOI":"10.1126\/science.aaa1348"},{"key":"2026071212035018731_j_raon-2022-0021_ref_023","doi-asserted-by":"crossref","unstructured":"Sykes AJ, Wlodek C, Trickey A, Clayton GL, Oakley A. Growth rate of clinically diagnosed superficial basal cell carcinoma and changes in dermoscopic features over time. Australas J Dermatol 2020; 61: 330-6. doi: 10.1111\/AJD.13352","DOI":"10.1111\/ajd.13352"},{"key":"2026071212035018731_j_raon-2022-0021_ref_024","doi-asserted-by":"crossref","unstructured":"Gehl J, Sersa G, Matthiessen LW, Muir T, Soden D, Occhini A, et al. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncol 2018; 57: 874-82. doi: 10.1080\/0284186X.2018.1454602","DOI":"10.1080\/0284186X.2018.1454602"},{"key":"2026071212035018731_j_raon-2022-0021_ref_025","doi-asserted-by":"crossref","unstructured":"Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365-76. doi: 10.1093\/JNCI\/85.5.365","DOI":"10.1093\/jnci\/85.5.365"},{"key":"2026071212035018731_j_raon-2022-0021_ref_026","unstructured":"Ah\u010dan U, Bertenjev I, Benedi\u010di\u010d A, Bremec T, Dugonik A, Gro\u0161elj A, et al. Recommendations for diagnosis, treatment and follow-up of patients with basal cell carcinoma. Onkologija 2019; 23: 74-94. doi: 10.25670\/oi2019-008on"},{"key":"2026071212035018731_j_raon-2022-0021_ref_027","unstructured":"European Medicines Agency; EMEA\/CHMP\/GTWP\/60436\/2007. Guideline on Follow-up of Patients Administered with Gene Therapy Medical Products. London; 2009; 1-12. [cited 2022 Feb 15]. Available at: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-follow-patients-administered-gene-therapy-medicinal-products_en.pdf"},{"key":"2026071212035018731_j_raon-2022-0021_ref_028","doi-asserted-by":"crossref","unstructured":"Algazi A, Bhatia S, Agarwala S, Molina M, Lewis K, Faries M, et al. Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients. Ann Oncol 2020; 31: 532-40. doi: 10.1016\/j.annonc.2019.12.008","DOI":"10.1016\/j.annonc.2019.12.008"},{"key":"2026071212035018731_j_raon-2022-0021_ref_029","doi-asserted-by":"crossref","unstructured":"Vandermeulen G, Marie C, Scherman D, Pr\u00e9at V. New generation of plasmid backbones devoid of antibiotic resistance marker for gene therapy trials. Mol Ther 2011; 19: 1942-9. doi: 10.1038\/MT.2011.182","DOI":"10.1038\/mt.2011.182"},{"key":"2026071212035018731_j_raon-2022-0021_ref_030","doi-asserted-by":"crossref","unstructured":"Vanpouille-Box C, Pilones KA, Wennerberg E, Formenti SC, Demaria S. In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 2015; 33: 7415-22. doi: 10.1016\/j.vaccine.2015.05.105","DOI":"10.1016\/j.vaccine.2015.05.105"},{"key":"2026071212035018731_j_raon-2022-0021_ref_031","doi-asserted-by":"crossref","unstructured":"Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G, et al. Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. Cancer Immunol Immunother 2015; 64: 1315-27. doi: 10.1007\/S00262-015-1724-2","DOI":"10.1007\/s00262-015-1724-2"},{"key":"2026071212035018731_j_raon-2022-0021_ref_032","doi-asserted-by":"crossref","unstructured":"Campana LG, Peric B, Mascherini M, Spina R, Kunte C, Kis E, et al. Combination of pembrolizumab with electrochemotherapy in cutaneous metastases from melanoma: a comparative retrospective study from the InspECT and Slovenian Cancer Registry. Cancers 2021; 13: 4289. doi:10.3390\/cancers13174289","DOI":"10.3390\/cancers13174289"},{"key":"2026071212035018731_j_raon-2022-0021_ref_033","doi-asserted-by":"crossref","unstructured":"Buchwald ZS, Wynne J, Nasti TH, Zhu S, Mourad WF, Yan W, et al. Radiation, immune checkpoint blockade and the abscopal effect: a critical review on timing, dose and fractionation. Front Oncol 2018; 8: 612. doi: 10.3389\/fonc.2018.00612","DOI":"10.3389\/fonc.2018.00612"},{"key":"2026071212035018731_j_raon-2022-0021_ref_034","doi-asserted-by":"crossref","unstructured":"Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013; 1: 365-72. doi: 10.1158\/2326-6066.CIR-13-0115","DOI":"10.1158\/2326-6066.CIR-13-0115"},{"key":"2026071212035018731_j_raon-2022-0021_ref_035","doi-asserted-by":"crossref","unstructured":"Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018; 24: 1845-51. doi: 10.1038\/s41591-018-0232-2","DOI":"10.1038\/s41591-018-0232-2"},{"key":"2026071212035018731_j_raon-2022-0021_ref_036","doi-asserted-by":"crossref","unstructured":"Plavc G, Jesenko T, Ora\u017eem M, Strojan P. Challenges in combining immunotherapy with radiotherapy in recurrent\/metastatic head and neck cancer. Cancers 2020; 12: 1-25. doi: 10.3390\/cancers12113197","DOI":"10.3390\/cancers12113197"}],"container-title":["Radiology and Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/reference-global.com\/pdf\/10.2478\/raon-2022-0021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T23:03:58Z","timestamp":1783897438000},"score":1,"resource":{"primary":{"URL":"https:\/\/reference-global.com\/article\/10.2478\/raon-2022-0021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,14]]},"references-count":36,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,8,14]]},"published-print":{"date-parts":[[2022,8,14]]}},"alternative-id":["10.2478\/raon-2022-0021"],"URL":"https:\/\/doi.org\/10.2478\/raon-2022-0021","relation":{},"ISSN":["1581-3207"],"issn-type":[{"value":"1581-3207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,14]]}}}