Abstract 1568: Developing a novel in vivo electroporation-based DNA vaccine utilizing a small molecule regulated immune switch

Abstract

Dendritic cell (DC) vaccines are a rapidly progressing area of translational research intended for developing new cancer treatment modalities. Although ex vivo DC-based vaccines have been extensively studied and clinically tested for the treatment of cancer, they are inherently limited by short DC lifespan after activation, labor-intensive production (requiring ex vivo manipulation of autologous cells), high cost and consequent limited accessibility to the patient. Therefore, we have attempted to develop portable, regulatable adjuvants that could be targeted to DCs and activated in situ. Development by our lab of an inducible variant of the costimulatory molecule, CD40 (iCD40), and a composite, inducible MyD88/CD40 (iMC) adjuvant, that also incorporates the universal Toll like receptor adapter, MyD88, have been shown to increase the potency and lifespan of DC vaccines. These inducible receptors act as in vivo DC “switches” that lead to the priming and robust expansion of antigen (Ag)-specific T-cells capable of eliminating pre-established tumors in mice. Despite the success of these DC “switch” systems, practicality and scalability of patient-tailored ex vivo DC vaccines remains a major hindrance to their widespread applicability. Therefore, the future of DC vaccines lies in the development of “off-the-shelf” methodologies, such as viral or non-viral vectors that can deliver adjuvants along with tumor antigens. DNA vaccines are attractive for this purpose owing to their elegant simplicity, ease of production, and lack of anti-vector immune responses. In order to successfully vaccinate patients with DNA, one must be able to deliver plasmid encoding therapeutic genes to target cells efficiently. In vivo electroporation is a relatively new technology just starting to be tested in clinical trials, and provides a safe, simple, and effective means by which to administer DNA vaccines. Data from our preliminary studies of the electroporative delivery of plasmids encoding the model antigen β-galactosidase (LacZ) in mice suggests that LacZ-specific T-cell responses are induced, and that upon tumor challenge, mice receiving prophylaxis via electroporation had slower tumor growth kinetics when compared to controls. Together, this preliminary data supports the notion that DNA vaccination with tumor Ag by electroporation may be a simple and effective “off-the-shelf” cancer vaccine strategy. Additionally, this vaccination strategy may be enhanced by the addition of the iMC adjuvant. Therefore, further investigation of intradermal electroporation is warranted by these findings, to better characterize the induced immune responses and better optimize vaccination

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1568. doi:1538-7445.AM2012-1568