Potentiation of electrochemotherapy effectiveness by immunostimulation with IL-12 gene electrotransfer in mice is dependent on tumor immune status

Uršič, Katja; Kos, Špela; Kamenšek, Urška; Čemažar, Maja; Miceska, Simona; Markelc, Boštjan; Buček, Simon; Starešinič, Barbara; Prevodnik, Veronika Kloboves; Heller, Richard; Serša, Gregor

doi:10.1016/j.jconrel.2021.03.009

Cited by 30 publications

(58 citation statements)

References 40 publications

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“…A similar result was observed when comparing more immunogenic SA-1 and less immunogenic TS/A tumours, with significant differences in the complete response rate [75]. Our recent study [47] also indicates a correlation between immune status and responsiveness to ECT. The more immunogenic tumours with higher immune infiltrate were more responsive to ECT.…”

Section: Immune Infiltratesupporting

confidence: 83%

“…Our recent murine study on ECT suggests that immunologically important tumour cell features, such as mutational burden and the expression of MHC-1, influence the response to ECT. Namely, ECT was more effective in more-immunogenic CT26 tumours compared with lessimmunogenic 4T1 and B16F10 melanoma [47]. Furthermore, the study indicated that ECT increases MHC-1 and PD-L1 expression and thus favourably predisposes tumours to immunotherapies.…”

Section: Immunologically Important Tumour Cell Featuresmentioning

confidence: 86%

“…Assessment of baseline tumour immunogenicity [93] and the characteristics of the local immune infiltrate [94,95] are potentially relevant information. Presumably, more immunogenic tumours exhibit a better response to ECT [75,47]. Furthermore, the induced immune response may vary upon the chemotherapeutic drug used and the treatment parameters, such as pulse parameters and the route of drug administration [56,96].…”

Section: Tumour Immune Statusmentioning

confidence: 99%

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Biological factors of the tumour response to electrochemotherapy: Review of the evidence and a research roadmap

Serša

Uršič

Čemažar

et al. 2021

European Journal of Surgical Oncology

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The beneficial effects of electrochemotherapy (ECT) for superficial tumours and, more recently, deepseated malignancies in terms of local control and quality of life are widely accepted. However, the variability in responses across histotypes needs to be explored. Currently, patient selection for ECT is based on clinical factors (tumour size, histotype, and exposure to previous oncological treatments), whereas there are no biomarkers to predict the response to treatment. In this field, two major areas of investigation can be identified, i.e., tumour cell characteristics and the tumour microenvironment (vasculature, extracellular matrix, and immune infiltrate). For each of these areas, we describe the current knowledge and discuss how to foster further investigation. This review aims to provide a summary of the currently used guiding clinical factors and delineates a research roadmap for future studies to identify putative biomarkers of response to ECT. These biomarkers may allow researchers to improve ECT practice by customising treatment parameters, manipulating the tumour and its microenvironment, and exploring novel therapeutic combinations.

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Section: Immune Infiltratesupporting

confidence: 83%

Section: Immunologically Important Tumour Cell Featuresmentioning

confidence: 86%

Section: Tumour Immune Statusmentioning

confidence: 99%

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Biological factors of the tumour response to electrochemotherapy: Review of the evidence and a research roadmap

Serša

Uršič

Čemažar

et al. 2021

European Journal of Surgical Oncology

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“…For example, it was shown that a higher number of CD8+ cells infiltrating tumors prior to ECT treatment was associated with better local response (7 responders of 9 treated—WHO criteria) when compared to the low presence of those cells (1 responder of 6 treated). Interestingly, the infiltration of FOXP3+ cells was not associated with ECT local response, however, it was significantly associated to the development of visceral metastasis [ 178 ], corroborating similar results obtained by Ursic and colleagues (2021) in three different tumor models treated by ECT, where the more immunogenic CT26 tumors had better outcomes when compared with less immunogenic 4T1 and B16F10 tumors [ 179 ]. In addition, in a comparative study of a murine model of sarcoma (immunogenic) and carcinoma (less immunogenic) treated by ECGT of IT cisplatin plus single or multiple IM IL-12 GET, it was demonstrated that the antitumor effect depends in part on the immunogenicity of the treated tumor, indicating that more immunogenic tumors had a better response and higher cure rate [ 90 ].…”

Section: Variability Of Responses In Ep-related Therapiessupporting

confidence: 76%

Clinical Applications and Immunological Aspects of Electroporation-Based Therapies

et al. 2021

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Reversible electropermeabilization (RE) is an ultrastructural phenomenon that transiently increases the permeability of the cell membrane upon application of electrical pulses. The technique was described in 1972 by Neumann and Rosenheck and is currently used in a variety of applications, from medicine to food processing. In oncology, RE is applied for the intracellular transport of chemotherapeutic drugs as well as the delivery of genetic material in gene therapies and vaccinations. This review summarizes the physical changes of the membrane, the particularities of bleomycin, and the immunological aspects involved in electrochemotherapy and gene electrotransfer, two important EP-based cancer therapies in human and veterinary oncology.

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“…Therefore, its combination with either ICIs or other forms of immunotherapy is of potential interest [ 20 , 21 ]. Furthermore, in preclinical studies, the in situ vaccination effect of ECT was proven, which can be boosted by adjuvant immunogenic therapy [ 20 , 21 , 22 , 23 ]. The first clinical experiences have demonstrated the feasibility and safety of the combination of ICIs with ECT [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Combination of Pembrolizumab with Electrochemotherapy in Cutaneous Metastases from Melanoma: A Comparative Retrospective Study from the InspECT and Slovenian Cancer Registry

Campana

Perić

Mascherini

et al. 2021

Cancers

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Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC–IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.

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Potentiation of electrochemotherapy effectiveness by immunostimulation with IL-12 gene electrotransfer in mice is dependent on tumor immune status

Cited by 30 publications

References 40 publications

Biological factors of the tumour response to electrochemotherapy: Review of the evidence and a research roadmap

Biological factors of the tumour response to electrochemotherapy: Review of the evidence and a research roadmap

Clinical Applications and Immunological Aspects of Electroporation-Based Therapies

Combination of Pembrolizumab with Electrochemotherapy in Cutaneous Metastases from Melanoma: A Comparative Retrospective Study from the InspECT and Slovenian Cancer Registry

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