Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: a first-in-human clinical trial protocol

Ales Groselj, Masa Bosnjak, Tanja Jesenko, Maja Cemazar, Bostjan Markelc, Primoz Strojan, Gregor Sersa, Ales Groselj, Masa Bosnjak, Tanja Jesenko, Maja Cemazar, Bostjan Markelc, Primoz Strojan, Gregor Sersa

Abstract

Background: 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).

Patients and methods: 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.

Conclusions: 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.

Keywords: basal cell carcinoma; gene electrotransfer; gene therapy; head and neck region; interleukin 12.

© 2022 Ales Groselj, Masa Bosnjak, Tanja Jesenko, Maja Cemazar, Bostjan Markelc, Primoz Strojan, Gregor Sersa, published by Sciendo.

Figures

Figure 1
Figure 1
Clinical trial design. CTCAE v.5 = Common Terminology Criteria for Adverse Events version 5.0; CR = complete response; EORTC QLQ-C30 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30; PR = partial response; PD = progressive disease; SD = stable disease

References

    1. 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.
    1. Nguyen KG, Vrabel MR, Mantooth SM, Hopkins JJ, Wagner ES, Gabaldon TA. Localized interleukin-12 for cancer immunotherapy. Front Immunol. 2020;11:575597. doi: 10.3389/fimmu.2020.575597. et al.
    1. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB. Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production. Blood. 1997;90:2541–8. doi: 10.3389/fimmu.2020.575597. et al.
    1. Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK. 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. et al.
    1. Spanggaard I, Snoj M, Cavalcanti A, Bouquet C, Sersa G, Robert C. 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. et al.
    1. Yarmush ML, Golberg A, Serša G, Kotnik T, Miklavčič 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.
    1. Rosazza C, Haberl Meglic S, Zumbusch A, Rols M-P, Miklavcic D. Gene electrotransfer: a mechanistic perspective. Curr Gene Ther. 2016;16:98–129. 0.2174/1566523216666160331130040.
    1. Canton DA, Shirley S, Wright J, Connolly R, Burkart C, Mukhopadhyay A. Melanoma treatment with intratumoral electroporation of tavokinogene telseplasmid (pIL-12, tavokinogene telseplasmid) Immunother. 2017;9:1309–21. doi: 10.2217/imt-2017-0096. et al.
    1. Bhatia S, Longino N V., Miller NJ, Kulikauskas R, Iyer JG, Ibrani D. 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. et al.
    1. Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12. Curr Gene Ther. 2010;10:300–11. doi: 10.2174/156652310791823425.
    1. Telli ML, Nagata H, Wapnir I, Acharya CR, Zablotsky K, Fox BA. 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. et al.
    1. Greaney SK, Algazi AP, Tsai KK, Takamura KT, Chen L, Twitty CG. 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. et al.
    1. Algazi AP, Twitty CG, Tsai KK, Le M, Pierce R, Browning E. 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. et al.
    1. 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.
    1. Kos S, Bosnjak M, Jesenko T, Markelc B, Kamensek U, Znidar K. 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. et al.
    1. 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.
    1. Clover AJP, Salwa SP, Bourke MG, McKiernan J, Forde PF, O’Sullivan ST. 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. et al.
    1. Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Kaatz M. 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. et al.
    1. Jayaraman SS, Rayhan DJ, Hazany S, Kolodney MS. Mutational landscape of basal cell carcinomas by whole-exome sequencing. J Invest Dermatol. 2014;134:213. doi: 10.1038/JID.2013.276. 20.
    1. Clover AJP, de Terlizzi F, Bertino G, Curatolo P, Odili J, Campana LG. 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. et al.
    1. Bertino G, Sersa G, De Terlizzi F, Occhini A, Plaschke CC, Groselj A. 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. et al.
    1. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ. 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. et al.
    1. 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.
    1. Gehl J, Sersa G, Matthiessen LW, Muir T, Soden D, Occhini A. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncol. 2018;57:874–82. doi: 10.1080/0284186X.2018.1454602. et al.
    1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ. 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. et al.
    1. Ahčan U, Bertenjev I, Benedičič A, Bremec T, Dugonik A, Grošelj A. Recommendations for diagnosis, treatment and follow-up of patients with basal cell carcinoma. Onkologija. 2019;23:74–94. doi: 10.25670/oi2019-008on. et al.
    1. Guideline on Follow-up of Patients Administered with Gene Therapy Medical Products. London: 2009. pp. 1–12. European Medicines Agency; EMEA/CHMP/GTWP/60436/2007. –. [cited 2022 Feb 15]. Available at.
    1. Algazi A, Bhatia S, Agarwala S, Molina M, Lewis K, Faries M. 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. et al.
    1. Vandermeulen G, Marie C, Scherman D, Préat 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.
    1. 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.
    1. Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G. 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. et al.
    1. Campana LG, Peric B, Mascherini M, Spina R, Kunte C, Kis E. 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. et al.
    1. Buchwald ZS, Wynne J, Nasti TH, Zhu S, Mourad WF, Yan W. 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. et al.
    1. 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.
    1. Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018;24:1845–51. doi: 10.1038/s41591-018-0232-2. et al.
    1. Plavc G, Jesenko T, Oražem 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.

Source: PubMed

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