Dendritic Cells Transduced with an Adenoviral Vector Encoding a Model Tumor-Associated Antigen for Tumor Vaccination

Abstract

Evaluation of the potential role of dendritic cells (DCs) as adjuvants for tumor vaccination has focused primarily on techniques that load DCs with peptide tumor antigens. Our aim has been to optimize the induction of antitumor immunity by enhancing the ability of DCs to present tumor-associated antigens endogenously to the afferent lymphatic system 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 with an Ad vector expressing the β-galactosidase gene and still retain their physiologic and phenotypic characteristics. Furthermore, we demonstrated 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 model, we have shown that a single injection of 10⁵–4 × 10⁶ DCs transduced with an Ad vector expressing PymT provided complete and specific protection against tumor cell challenge in 100% of vaccinated animals. Immunization against the PymT tumor by injection with the PymT expressing Ad vector alone resulted in varying degrees of effectiveness, was highly dependent upon the route of administration, and led to significant hepatic toxicity that was not seen in mice immunized with DC transduced 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 stimulate a potent antitumor response.

Overview summary

Tumor immunotherapy has been advanced greatly by the discovery of tumor-associated antigens. It is now possible to devise strategies to prepare tumor vaccines consisting of defined proteins for cancer treatment. However, this approach is limited by our inability to administer the antigenic proteins effectively. We have demonstrated that dendritic cells transduced with an adenovirus expressing a tumor antigen can completely protect the host from tumor challenge, and this approach avoids the adenovirus-associated hepatic toxicity caused by the direct administration of adenoviral vectors. Thus, we describe a flexible approach to tumor vaccination that has a broad applicability to any vaccination procedure involving defined antigens.