ANTIGEN EXPRESSION BY DENDRITIC CELLS CORRELATES WITH THE THERAPEUTICEFFECTIVENESS OF A MODEL RECOMBINANT POXVIRUS TUMOR VACCINE

Recombinant poxviruses encoding tumor-associated antigens (TAA) are at tractive as candidate cancer vaccines, Their effectiveness, however, w ill depend upon expression of the TAA in appropriate antigen-presentin g cells, We have used a murine model in which the TAA is beta-galactos idase (beta-gal) and a panel of recombinant vaccinia viruses (rVV) in which beta-gal was expressed under early or late promoters at levels t hat varied over 500-fold during productive infections in tissue cultur e cells. Remarkably, only those rVV employing early promoters were cap able of prolonging the survival of mice bearing established tumors exp ressing the model TAA, Late promoters were ineffective regardless of t heir determined promoter strength, The best results were obtained when beta-gal was regulated by a strong early promoter coupled to a strong late promoter, When a variety of cell types were infected with the pa nel of viruses in vitro, dendritic cells were found to express beta-ga l only under the control of the early promoters even though late promo ters were intrinsically more active in other cell types, Furthermore, in a functional assay, dendritic cells infected in vitro with rVV enco ding beta-gal regulated by an early promoter activated beta-gal-specif ic cytotoxic T lymphocytes, whereas similar rVV with a late promoter-r egulated gene did not, These data indicate that promoter strength per se is not the most critical quality of a recombinant poxvirus-based tu mor vaccine and that the use of promoters capable of driving the produ ction of TAA in ''professional'' antigen presenting cells may be cruci al.