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Multimodality Immunization Approaches 135
near-exclusive reliance on cross-priming—except when strategies to increase the
influx of APCs are deployed (32). In contrast, injection of plasmid into dendritic
cell (DC)-rich areas such as dermis results in the induction of MHC class I–
restricted immunity via conventional processing and priming pathways (29,30).
The relative potential of these pathways is suggested by dose-effect, adoptive celltransfer
experiments, in which in situ transfected professional APCs and somatic
cells, respectively, were separately infused in naïve mice. While non-APCs
yielded a limited immune response, the transgene-expressing, professional APCs
induced a significantly increased response (29) illustrating the concept that in the
course of DNA immunization, the conventional processing/priming pathway has a
higher potential from this standpoint, as compared to cross-processing/crosspriming.
This has been strongly supported by reports showing that direct intrasplenic
or LN administration of naked plasmid resulted in increased immunity, as
assessed in a dose-effect fashion (33). It is likely that targeted administration of
naked plasmid to APC-rich tissues results in increased numbers of competent
APCs presenting the antigen directly to specific T cells, even if the overall number
of host cells effectively transfected is not superior over those achieved by intramuscular
or subcutaneous administration. In fact, a recent study provided further
support to this concept by demonstrating that the use of a device to increase the
exposure of dermal APCs to plasmid vaccine, as opposed to conventional bolus
injection, resulted in increased immunity (34). Strikingly, despite the fact that
intramuscular injection resulted in higher antigen expression for a prolonged
interval (weeks), intradermal administration using a tattoo device resulted in a
relatively reduced antigen expression over only a few days; however, it was far
more effective in inducing T-cell immunity (35).
The multiplicity of mechanisms by which plasmids elicit immune
responses, depending on the route of administration and other factors, results in a
number of limiting steps relative to the magnitude of the resulting immune
response (Fig. 1). These can be thus addressed by various means, as listed in
Table 1. More important, addressing limiting factors on individual basis may not
be enough to effectively improve the potency of DNA vaccines; instead, significantly
superior strategies must troubleshoot as many as possible, if not all,
rate-limiting factors.
ADVANTAGES OF PLASMID VECTORS AS THERAPEUTIC
VACCINES FOR CANCER
Among different vaccine forms for treating cancer, DNA vaccine has several
advantages such as immunogenicity, intrinsic adjuvant effect, capacity for harboring
larger or multiple antigens and ease to manipulate, preferred safety
profile, excellent stability, and inexpensive manufacturing cost.
The cellular arm of the immune response, the focus of active immunotherapy
employing DNA vaccination, results from uptake of plasmids into cells
(DCs, Langerhans cells, and muscle cells) (30,31), where the encoding target