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*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037;
Vanderbilt University Medical Center, Nashville, TN 37232;
Department of Pediatrics, Whittier Institute, University of California, La Jolla, CA 92037;
Charité Children’s Hospital, Berlin Germany; and
¶ Lexigen Pharmaceuticals, Lexington, MA 02173
A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and
CD40 ligand trimer achieved effective tumor-protective immunity against
murine colon carcinoma in CEA-transgenic mice by activating both naive
T cells and dendritic cells. Peripheral T cell tolerance to CEA was
broken in a prophylactic model by this novel, dual-function DNA
vaccine, whose efficacy was further enhanced by boosts with a
recombinant Ab-IL-2 fusion protein (huKS1/4-IL-2). These conclusions
are supported by four lines of evidence. First, a lethal challenge of
MC38-CEA-KS Ag murine colon carcinoma cells was for the first
time completely rejected in 100% of experimental animals treated by
oral gavage of this DNA vaccine carried by attenuated Salmonella
typhimurium, followed by five boosts with huKS1/4-IL-2. Second,
specific activation of dendritic cells was indicated by their marked
up-regulation in expression of costimulatory molecules B7.1 (CD80),
B7.2 (CD86), and ICAM-1. Third, a decisive increase over control values
was observed in both MHC class I Ag-restricted cytotoxicity of CTLs
from successfully vaccinated mice and secretion of proinflammatory
cytokines IFN-
and IL-12. Fourth, activation of CTLs was augmented,
as indicated by up-regulation of activity markers LFA-1, CD25, CD28,
and CD69. Taken together, these results suggest that a dual-function
DNA vaccine encoding CEA and CD40 ligand trimer combined with
tumor-targeted IL-2 may be a promising strategy for the rational
development of DNA-based cancer vaccines for future clinical
applications.
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