Controlled Gene Delivery Can Enhance Therapeutic Outcome for Cancer Immune Therapy for Melanoma
Shawna A. Shirley,
Cathryn G. Lundberg,
Effective delivery still remains a major hurdle in the development of gene based therapies. While
technological advances have occurred that have improved delivery in general, there is still a need for controlled
delivery in order to achieve therapeutic effects. Gene electrotransfer (GET) can be utilized to accomplish
this. Careful selection of parameters used for delivery such as amplitude, duration and number of
pulses as well as plasmid construct can be manipulated in order to achieve appropriate levels of local expression.
Previously we have shown that direct delivery of the therapeutic cytokine, interleukin 12 (IL-12), to tumors using
electrotransfer can generate local and systemic anti-tumor effects in pre-clinical and clinical studies. Using this model
we hypothesized that modulating local gene expression using GET can affect therapeutic outcome. To test this, we used
multiple GET protocols and plasmids to achieve varying levels of local IL-12 expression. We found that high local gene
expression did not give rise to a better therapeutic outcome. This suggests the level and possibly the duration of gene expression
are important in mediating the host immune response against melanoma. These data also emphasize the importance
of considering the desired immune outcome of the therapy when selecting parameters for GET.
Keywords: Cytokine, electrotransfer, gene therapy, immunotherapy, interleukin-12, melanoma.
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