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Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer.

Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G, Miklavcic D - Cancer Immunol. Immunother. (2015)

Bottom Line: The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue.In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment.Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000, Ljubljana, Slovenia, gsersa@onko-i.si.

ABSTRACT
Electroporation is a platform technology for drug and gene delivery. When applied to cell in vitro or tissues in vivo, it leads to an increase in membrane permeability for molecules which otherwise cannot enter the cell (e.g., siRNA, plasmid DNA, and some chemotherapeutic drugs). The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue. Therefore, the understanding of different principles of drug and gene delivery is necessary and needs to be taken into account according to the specificity of their delivery to tumors and/or normal tissues. Based on the current knowledge, electrochemotherapy (a combination of drug and electric pulses) is used for tumor treatment and has shown great potential. Its local effectiveness is up to 80 % of local tumor control, however, without noticeable effect on metastases. In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment. Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases. Therefore, we propose a combination of electrochemotherapy with peritumoral IL-12 electrotransfer, as a proof of principle, using electrochemotherapy boosted with immunogene electrotransfer as in situ vaccination for successful tumor treatment.

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Proposed model for electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. ECT electrochemotherapy, GET gene electrotransfer
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Fig3: Proposed model for electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. ECT electrochemotherapy, GET gene electrotransfer

Mentions: Some studies have also explored the combination of local therapies with the gene electrotransfer of immunomodulatory genes. The combinations with either radiotherapy or electrochemotherapy were explored. The strategy was similar, radiosensitization or chemosensitization by immunoadjuvant therapy that boosted the immune response of the organism against tumor [77, 91–96]. A good potentiation of the radiation response and electrochemotherapy was noted, but the underlying immunomodulatory mechanisms were not explored. The knowledge of the mechanisms underlying the elicited immune response by local therapy, such as electrochemotherapy, would lead into the proper scheduling of suitable combination therapies for elicitation of systemic immune response. Thus, appropriate dosage of the pDNA encoding immunomodulatory molecules and the scheduling of it need to be determined [97]. Additionally, suitable biomarkers that would predict the treatment response are needed. Currently, it seems that several consecutive immunogene therapies are necessary. Indeed, in preclinical studies, it was shown that at least three consecutive immunogene electrotransfers should be performed, one prior to electrochemotherapy and two consecutive ones thereafter [78]. Skin gene electrotransfer is very appealing, since the skin is a tissue with vast amounts of immune cells capable of eliciting an efficient vaccination and boosting effect. Some studies have already shown that DC activation in the treatment of melanoma may be an exciting approach [98] (Fig. 3).Fig. 3


Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer.

Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G, Miklavcic D - Cancer Immunol. Immunother. (2015)

Proposed model for electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. ECT electrochemotherapy, GET gene electrotransfer
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4554735&req=5

Fig3: Proposed model for electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. ECT electrochemotherapy, GET gene electrotransfer
Mentions: Some studies have also explored the combination of local therapies with the gene electrotransfer of immunomodulatory genes. The combinations with either radiotherapy or electrochemotherapy were explored. The strategy was similar, radiosensitization or chemosensitization by immunoadjuvant therapy that boosted the immune response of the organism against tumor [77, 91–96]. A good potentiation of the radiation response and electrochemotherapy was noted, but the underlying immunomodulatory mechanisms were not explored. The knowledge of the mechanisms underlying the elicited immune response by local therapy, such as electrochemotherapy, would lead into the proper scheduling of suitable combination therapies for elicitation of systemic immune response. Thus, appropriate dosage of the pDNA encoding immunomodulatory molecules and the scheduling of it need to be determined [97]. Additionally, suitable biomarkers that would predict the treatment response are needed. Currently, it seems that several consecutive immunogene therapies are necessary. Indeed, in preclinical studies, it was shown that at least three consecutive immunogene electrotransfers should be performed, one prior to electrochemotherapy and two consecutive ones thereafter [78]. Skin gene electrotransfer is very appealing, since the skin is a tissue with vast amounts of immune cells capable of eliciting an efficient vaccination and boosting effect. Some studies have already shown that DC activation in the treatment of melanoma may be an exciting approach [98] (Fig. 3).Fig. 3

Bottom Line: The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue.In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment.Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000, Ljubljana, Slovenia, gsersa@onko-i.si.

ABSTRACT
Electroporation is a platform technology for drug and gene delivery. When applied to cell in vitro or tissues in vivo, it leads to an increase in membrane permeability for molecules which otherwise cannot enter the cell (e.g., siRNA, plasmid DNA, and some chemotherapeutic drugs). The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue. Therefore, the understanding of different principles of drug and gene delivery is necessary and needs to be taken into account according to the specificity of their delivery to tumors and/or normal tissues. Based on the current knowledge, electrochemotherapy (a combination of drug and electric pulses) is used for tumor treatment and has shown great potential. Its local effectiveness is up to 80 % of local tumor control, however, without noticeable effect on metastases. In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment. Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases. Therefore, we propose a combination of electrochemotherapy with peritumoral IL-12 electrotransfer, as a proof of principle, using electrochemotherapy boosted with immunogene electrotransfer as in situ vaccination for successful tumor treatment.

Show MeSH
Related in: MedlinePlus