A dual-function DNA vaccine encoding carcinoembryonic antigen and CD40 ligand trimer induces T cell-mediated protective immunity against colon cancerin carcinoembryonic antigen-transgenic mice

A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and CD40 li gand trimer achieved effective tumor-protective immunity against murine col on carcinoma in CEA-transgenic mice by activating both naive T cells and de ndritic cells. Peripheral T cell tolerance to CEA was broken in a prophylac tic model by this novel, dual-function DNA vaccine, whose efficacy was furt her enhanced by boosts with a recombinant Ab-IL-2 fusion protein (huKS1/4-I L-2). These conclusions are supported by four lines of evidence. First, a l ethal challenge of MC38-CEA-KS Ag murine colon carcinoma cells was for tile first time completely rejected in 100% of experimental animals treated by oral gavage of this DNA vaccine carried by attenuated Salmonella typhimuriu m, followed by five boosts with huKS1/4-IL-2. Second, specific activation o f 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-r estricted cytotoxicity of CTLs from successfully vaccinated mice and secret ion of proinflammatory cytokines IFN-gamma 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 tumo r-targeted IL-2 may be a promising strategy for the rational development of DNA-based cancer vaccines for future clinical applications.