A primary focus of current research on genetic vaccination is the development of strategies to activate nonresponsive antigen specific T-cells. The first consideration of any tumor therapy is the choice of cancer antigen in a genetic construct. Much effort has been devoted to the optimization of TAAs, and this work is described in detail elsewhere (11,12). Despite this optimization and the large number of genetic vaccine clinical trials for cancera, DNA vaccination in humans has not elicited as potent immune responses as observed in smaller animal models. For example, eliciting an immune response with intramuscular (im) naked DNA vaccination (plasmid DNA with no delivery vehicle) requires as much as 5mg of plasmid DNA in nonhuman primates (13), but only 50 to 300 ^g in mice (4). Although high doses of plasmid are generally well tolerated in humans (14), the need for additional technologies to boost the effectiveness of genetic vaccines is apparent.
One of the earliest advances in DNA delivery was the gene gun. This device delivers DNA coated onto the surface of tiny gold beads which are then accelerated to a high speed into the skin by a high pressure helium source (15). Immune responses elicited by vaccination using gene gun delivery to the skin requires much less plasmid DNA, on the order of several hundred to several thousand times less than naked DNA (4,16). This may partially result from the large amount of dendritic cells present in the skin, called Langerhan's cells (17). However, immune responses to gene gun vaccines are usually Th2 polarized, and there are questions as to the viability of this technology commercially.
Viral vectors are inherently efficient at gene delivery and are powerfully immunogenic. However, the potential toxicity of viral vectors is well known, and is particularly relevant aThere are currently 114 clinical trials worldwide for the treatment of cancer, representing 89% of all genetic vaccine clinical trials. (Journal of Gene Medicine trial online database.)
in patients with compromised immunity resulting from the progression of cancer and chemotherapy. Furthermore, the common requirement of multiple vaccinations can be problematic using viral vectors. Recently, it was shown that restimulation with adeno-virally transduced DCs actually decreased the antigen-specific immune response in favor of strong antiadenovirus specific immune reactions in melanoma patients (18). Pre-existing immunity can also inhibit delivery using viral vectors. Attenuated bacteria has also shown promise for vaccine delivery, but are associated with safety concerns as well (19).
Synthetic nonviral delivery of plasmid DNA vaccines, although potentially safer, has proven much less effective at eliciting strong immune responses. However, recent advances have significantly increased their efficacy and therapeutic potential. It is these current advances which this chapter focuses on.
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