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Skin Electrovaccination: Effects on Transgene Expression, DNA Persistence and Local Tissue Environment

ABSTRACT: Background: The use of electrical pulses to enhance uptake of molecules into living cells have been used for decades. This technique, often referred to as electroporation, has become an increasingly popular method to enhance in vivo DNA delivery for both gene. therapy applications as well as for delivery of vaccines against both infectious diseases and cancer. In vivo electrovaccination is currently being investigated in several clinical trials, including DNA delivery to healthy volunteers. However, the mode of action at molecular level is not yet fully understood. Methodology/Principal Findings: This study investigates intradermal DNA electrovaccination in detail and describes the effects on expression of the vaccine antigen, plasmid persistence and the local tissue environment. Gene profiling of the vaccination site is currently being evaluated in clinical trials, the data provided will be of high significance.. Conclusions/Significance: This study provides important insights to how DNA delivery by intradermal electrovaccination affects the local immunological responses of the skin, transgene expression and clearance of the plasmid. As the described vaccination approach showed that the combination of DNA and electroporation induced a significant up-regulation of pro-inflammatory genes. In vivo imaging of luciferase activity after electrovaccination demonstrated a rapid onset (minutes) and a long duration (months) of transgene expression. However, when the more immunogenic prostate specific antigen (PSA) was co-administered, PSA-specific T cells were induced and concurrently the luciferase expression became undetectable. Electroporation did not affect the long-term persistence of the PSA-expressing plasmid.

ORGANISM(S): Mus musculus

PROVIDER: GSE18003 | GEO | 2009/09/11

SECONDARY ACCESSION(S): PRJNA119287

REPOSITORIES: GEO

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Project description:Predicting Outcomes of Prostate Cancer Immunotherapyby Personalized Mathematical Models Natalie Kronik1¤, Yuri Kogan1, Moran Elishmereni1, Karin Halevi-Tobias1, Stanimir Vuk-Pavlovic ́2.,Zvia Agur1*.1Institute for Medical BioMathematics, Bene Ataroth, Israel,2College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America Abstract Background:Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients.We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simplemathematical models.Methodology/Principal Findings:We developed a general mathematical model encompassing the basic interactions of avaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cellvaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes inprostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were dividedinto each patient’s training set and his validation set. The training set, used for model personalization, contained thepatient’s initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized modelswere simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set.The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients(the coefficient of determination between the predicted and observed PSA values wasR2= 0.972). The model could notaccount for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validatedpersonalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccinationregimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Conclusions/Significance:Using a few initial measurements, we constructed robust patient-specific models of PCaimmunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value andfeasibility of individualized model-suggested immunotherapy protocols.

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Skin Electrovaccination: Effects on Transgene Expression, DNA Persistence and Local Tissue Environment

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