V. Bronte et al., ANTIGEN EXPRESSION BY DENDRITIC CELLS CORRELATES WITH THE THERAPEUTICEFFECTIVENESS OF A MODEL RECOMBINANT POXVIRUS TUMOR VACCINE, Proceedings of the National Academy of Sciences of the United Statesof America, 94(7), 1997, pp. 3183-3188
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.