Submitted January 28, 2008
Accepted September 10, 2008
Enhancement of DNA tumor vaccine efficacy by gene gun-mediated co-delivery of threshold amounts of plasmid-encoded helper antigen
Wolfgang W Leitner, Matthew C Baker, Thomas L Berenberg, Michael C Lu, P Josef Yannie, and Mark C Udey*
Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD, United States
* Corresponding author; email: udey{at}helix.nih.gov.
Nucleic acid-based vaccines are effective in infectious disease models, but have yielded disappointing results in tumor models when tumor-associated self-antigens are employed. Incorporation of helper epitopes derived from foreign antigens into tumor vaccines might enhance the immunogenicity of DNA vaccines without increasing toxicity, but this approach raises practical and theoretical concerns. Generation of fusion constructs encoding both tumor and helper antigens may be difficult, and resulting proteins have unpredictable physical and immunological properties. In addition, simultaneous production of equal amounts of highly immunogenic helper and weakly immunogenic tumor antigens in situ could favor development of responses against the helper antigen rather than the weaker antigen of interest. We assessed the ability of two helper antigens (beta-galactosidase or Fragment C of tetanus toxin) encoded by one plasmid to augment the response to a self-antigen (lymphoma-associated T cell receptor) encoded by a separate plasmid after co-delivery into skin by gene gun. This approach allowed adjustment of the relative ratios of helper and tumor antigen plasmids to optimize any observed helper effect. Incorporation of threshold (minimally immunogenic) amounts of helper antigen plasmid into a DNA vaccine regimen dramatically increased T cell-dependent protective immunity initiated by plasmid-encoded tumor-associated T cell receptor antigen. This simple strategy can easily be incorporated into future vaccine trials in experimental animals and possibly in humans.
