Background Electrochemotherapy (ECT) is a local cancer treatment based on electroporation where the electric field is used to enhance cell membrane permeability and thereby facilitating the ...transition of chemotherapeutic agents into the cell. For the treatment of non-melanoma skin cancer, a standard dosage of 15,000 IU/m2 bleomycin (BLM) is used. The aim of the present study was to evaluate the long-term ECT response in the group of elderly patients with non-melanoma skin cancer treated with a reduced dose of BLM in comparison to the outcome in the patients treated with the standard dose of BLM. Patients and methods Twenty-eight patients older than 65 years, with a total of 52 non-melanoma skin lesions were included in the study. Twelve patients (24 lesions) in the experimental group received a reduced dose of BLM (10,000 IU/m2), 16 patients (28 lesions) were treated with a standard dose of BLM (15,000 IU/m2). Results No statistically significant difference in tumor control was observed between both groups. In the experimental group, tumors recurred in 39.0% of treated lesions in a median follow-up time of 28 months. In the control group, the recurrence rate of treated lesions was 15.4% in a median follow-up time of 40 months. Conclusions ECT with a reduced dose of BLM is a feasible treatment option for elderly patients with equal efficacy to standard dose treatment and should be considered as a treatment modality in advanced aged patients with comorbidities, where overall life expectancy is poor.
Genska terapija postaja čedalje bolj zanimiva tudi v onkologiji. Med aplikacijami je morda najzanimivejša imunostimulacija. Pripravimo lahko plazmidno DNA, ki nosi zapis za različne imunostimulatorne ...molekule, ki jih vnesemo v celice tumorjev ali normalnih tkiv. Ta tkiva postanejo proizvajalci teh molekul, ki lahko delujejo lokalno ali pa se izločajo tudi sistemsko v krvni obtok. Ker plazmidna DNA ne prehaja celične membrane, so potrebni dostavni sistemi, virusni ali nevirusni. V naših študijah uporabljamo predvsem nevirusni dostavni sistem – elektroporacijo. Interlevkin 12 (IL-12) je eden od zanimivih citokinov, za katerega je znano protitumorsko delovanje s spodbujanjem imunskega odziva in antiangiogenim delovanjem. Namen projekta SmartGene.si je bil pripraviti plazmid z zapisom za interlevkin 12 (plazmid phIL12) in pripraviti vse potrebno za njegovo klinično testiranje za zdravljenje kožnih tumorjev. V konzorciju smo združili moči s partnerji z akademskega in industrijskega področja. Treba je bilo pripraviti plazmid za uporabo v humani onkologiji po zahtevah Evropske agencije za zdravila (EMA). Za prijavo klinične študije na Javno agencijo za zdravila in medicinske pripomočke (JAZMP) smo morali izvesti tudi vse neklinične raziskave o varnosti in učinkovitosti zdravila. Nato je bilo treba razviti postopek priprave zdravila, zagotoviti primerne prostore za pripravo in izvedbo postopka priprave zdravila. V treh letih smo dosegli vse te zastavljene cilje in dobili dovoljenje za izvajanje klinične študije na kožnih tumorjih, ki ga je izdala JAZMP na osnovi pozitivnega mnenja Komisije Republike Slovenije za medicinsko etiko. Zdaj poteka klinična študija faze I preizkušanja plazmida phIL12 na kožnih tumorjih glave in vratu z namenom preveriti varnost in sprejemljivost genskega elektroprenosa plazmida v tumorje. Cilj študije je prav tako določiti primeren odmerek zdravila, ki bi ga v nadaljnji klinični študiji uporabili kot adjuvantno zdravljenje k ablativnim terapijam, kot sta radioterapija ali elektrokemoterapija.
The study aims to demonstrate a combination of superselective catheterization and electrochemotherapy as a feasible and effective new technological approach in treating high-flow vascular ...malformations of the head and neck region.
In the patient with high-flow arteriovenous malformation of the lower lip, superselective catheterization was performed under general anesthesia. The microcatheter was used to administer 750 IU BLM intra-arterially into the feeding vessel. The whole malformation surface was then covered with 15 applications of electric pulses using the plate electrode.
Excellent response, without functional or aesthetic deficits, was obtained in 10 weeks. During this period, debridement and necrectomy were performed regularly on follow-up visits. The pain was managed with oral paracetamol and sodium metamizole.
Combining electrochemotherapy using bleomycin with superselective catheterization and arteriography is a feasible treatment option for high-flow vascular malformations in the head and neck region and could play a significant role in managing these challenging lesions.
The plasma concentration profile of bleomycin in the distribution phase of patients younger than 65 years is needed to determine the suitable time interval for efficient application of electric ...pulses during electrochemotherapy. Additionally, bleomycin concentrations in the treated tumors for effective tumor response are not known. In this study, the pharmacokinetic profile of bleomycin in the distribution phase in 12 patients younger than 65 years was determined. In 17 patients, the intratumoral bleomycin concentration was determined before the application of electric pulses. In younger patients, the pharmacokinetics of intravenously injected bleomycin demonstrated a faster plasma clearance rate than that in patients older than 65 years. This outcome might indicate that the lowering of the standard bleomycin dose of 15,000 IU/m2 with intravenous bleomycin injection for electrochemotherapy is not recommended in younger patients. Based on the plasma concentration data gathered, a time interval for electrochemotherapy of 5–15 min after bleomycin injection was determined. The median bleomycin concentration in tumors 8 min after bleomycin injection, at the time of electroporation, was 170 ng/g. Based on collected data, the reduction of the bleomycin dose is not recommended in younger patients; however, a shortened time interval for application of electric pulses in electrochemotherapy to 5–15 min after intravenous bleomycin injection should be considered.
The aim of this multicenter study was to evaluate the effectiveness and safety of electrochemotherapy (ECT) for the treatment of mucosal tumors in the head and neck.
A total of 71 patients with 84 ...nodules of different histologies in the oral cavity, pharynx and larynx treated by ECT were evaluated. The data were collected from the InspECT database from 10 participating centers throughout Europe.
Primary and recurrent/secondary tumors of different histologies were treated. The overall response rate was 65 %, with a 33 % complete response rate with limited side effects. The response rates of the primary and secondary tumors were not different. However, smaller tumors responded better than tumors larger than 3 cm in diameter. Furthermore, the tumors that were treated with curative intent responded significantly better than those treated with palliative intent.
This study demonstrated the feasibility, safety and effectiveness of ECT in a larger cohort of patients with mucosal lesions in the head and neck region. Based on the available data, ECT can be used for the treatment of recurrent and, in some cases, primary mucosal tumors located in the oral cavity, larynx, and pharynx. A better response was obtained in patients with smaller primary tumors treated with curative intent.
Abstract
Immunotherapies with monoclonal antibodies (checkpoint inhibitors) are currently being intensively researched and have led to excellent response in many cases in various tumors. Another ...potential approach to immunotherapy is the targeted intratumoral administration of interleukin 12 (IL -12), a cytokine with proven anti-tumor activity. Due to its immunomodulatory effect, it can be used as an immunostimulatory component for in situ vaccination of local ablative therapies. We have developed a phIL12 plasmid without antibiotic resistance markers using a transgene for the human IL -12 p70 protein. The plasmid can be introduced intratumorally by gene electrotransfer. In gene electrotransfer, electrical pulses are applied to the tumor to deliver the plasmid DNA into the cells. Based on nonclinical studies of safety, pharmacokinetics, pharmacodynamics, tolerability, and immunogenicity, a phase I clinical trial of phIL12 gene electrotransfer was conducted (ISRCTN15479959, ClinicalTrials NCT05077033). The primary objective of the study is to evaluate the safety and tolerability of phIL12 gene electrotransfer in the treatment of basal cell carcinoma in patients with operable tumors of the head and neck. The study, an exploratory, dose-escalating Phase I study, will enroll 9 patients in three dose-escalating cohorts. Treatment consists of plasmid injection followed by application of electrical pulses to the tumors. Patients are monitored for 30 days, with tumors removed if a complete response is not achieved. To date, two cohorts of patients have completed the study. No adverse effects or treatment-related toxicities have been observed, and treatment has been well tolerated by patients. The results of this study will provide the basis for the use of phIL12 gene electrotransfer as adjuvant therapy to local ablative therapies to enhance their local effect and elicit a systemic response.
Citation Format: Gregor Sersa, Maja Cemazar, Crt Jamsek, Primoz Strojan, Tanja Jesenko, Masa Bosnjak, Ales Groselj. Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: A phase I clinical trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT115.
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