Download File - JOHN J. HADDAD, Ph.D.

7
Multimodality Immunization Approaches
to Improve on DNA Vaccines for Cancer
INTRODUCTION
Zhiyong Qiu and Kent A. Smith
Division of Translational Medicine, MannKind Corporation,
Valencia, California, U.S.A.
The discovery, more than a decade ago, that naked plasmid vectors expressing
exogenous genes can be utilized to elicit immune responses promoted an
unprecedented excitement and pursue of this strategy in preclinical and clinical
development of innovative biotherapeutics in infectious diseases (1–3), cancer
(4–7), and autoimmunity (8–10). An initial momentum resulting from promising
preclinical results has been somewhat diminished subsequently due to modest
efficacy data obtained in various clinical trials, particularly in prophylactic settings
(11,12). Nevertheless, features such as the apparent simplicity of mechanism of
action, intrinsic adjuvant properties, favorable safety profile, and ease in manufacturing,
all warrant a careful analysis of the limiting factors associated with
DNA vaccination with the purpose of designing novel strategies that leverage
these beneficial features.
One of the hallmarks of plasmid immunization is that the antigenpresenting
cells (APCs) have relatively prolonged exposure to low levels of antigen.
While this may lead to the generation of high-quality responses, it has been
difficult to obtain high-magnitude responses using such vaccines, even with
repeated booster doses, a phenomenon likely due to the relatively low levels of
epitope loading onto major histocompatibility complex (MHC) achieved with
131