The ability of dendritic cells (DC) to activate naive T-cells has made them targets for the design of enhanced vaccination protocols. DC loaded with tumor antigens in vitro and injected into recipients, have induced protective immune responses in several different animal models, and some encouraging preliminary data have been reported with DC-based vaccination trials in humans. However, the intensity and durability of these vaccines are usually modest. Currently attempts to improve the efficacy of the DC vaccines have focused upon enhancing the efficiency of loading DC with a diverse array of antigens, and improving upon the entry of the exogenous antigens into the MHC Class I pathway. A simple chemical modification of the antigen has been used here to enhance the amount and duration of the antigen bound to DC and to direct the linkage of antigens to the extracellular domains of receptors on surface of DC. The covalent linkage of antigens to receptors (which include ones that target both MHC Class I and II processing pathways) proceeds without loss of viability or function of the DC and results in the internalization of the bound antigen-receptor complexes.
The aim of this proposal is to establish whether the covalent linkage of antigens to DC significantly enhances the efficacy of a DC-based tumor vaccination strategy.
In Aim 1 mice immunized with DC loaded with a chemically modified surrogate tumor antigen, beta-galactosidase, (beta-gal) will be compared to mice immunized with DC loaded with unmodified beta-gal for their ability to resist a challenge with a beta-gal transfected tumor (i.e. protective efficacy of the vaccine).
In Aim 2 the ability of antigen covalently linked to DC to suppress and/or eradicate existing tumors will be assessed (i.e. therapeutic efficacy of the vaccine). In the final Aim, the protective and therapeutic efficacy of the enhanced and directed loading of DC will be tested using a bona fide tumor specific antigen, i.e. a B-cell tumor-associated immunoglobulin.
