DENDRITIC CELLS TRANSDUCED WITH AN ADENOVIRAL VECTOR ENCODING A MODELTUMOR-ASSOCIATED ANTIGEN FOR TUMOR VACCINATION

Evaluation of the potential role of dendritic cells (DCs) as adjuvants for tumor vaccination has focused primarily on techniques that load D Cs with peptide tumor antigens, Our aim has been to optimize the induc tion of antitumor immunity by enhancing the ability of DCs to present tumor-associated antigens endogenously to the afferent lymphatic syste m in the appropriate major histocompatibility complex (MHC)-restricted context. We have used replication-defective adenovirus vectors (Ads) to transduce DCs with various genes, including tumor antigen genes, We found that 90% of murine bone marrow derived-DCs could be infected wi th an Ad vector expressing the beta-galactosidase gene and still retai n their physiologic and phenotypic characteristics. Furthermore, we de monstrated that transgene expression was detectable in the spleen for at least 3 days following intravenous injection of Ad-transduced DCs. Using a polyoma middle T (PymT) transgenic murine mammary carcinoma mo del, we have shown that a single injection of 10(5)-4 x 10(6) DCs tran sduced with an Ad vector expressing PymT provided complete and specifi c protection against tumor cell challenge in 100% of vaccinated animal s, Immunization against the PymT tumor by injection with the PymT expr essing Ad vector alone resulted in varying degrees of effectiveness, w as highly dependent upon the route of administration, and led to signi ficant hepatic toxicity that was not seen in mice immunized with DC tr ansduced with the Ad vector, Our results suggest that: (i) DCs can be very efficiently modified by ex vivo Ad transduction to express tumor- specific antigens, (ii) such modified DCs appear nontoxic and stimulat e a potent antitumor response.