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In situ delivery of tumor-associated antigen (TAA) genes into dendritic cells (DC) has great potential as a generally applicable tumor vaccination approach. Although adenoviruses (Ad) are an attractive vaccine vehicle in this regard, Ad-mediated transduction of DCs is hampered by the lack of expression of the Ad receptor CAR on the DC surface. DC activation also requires interaction of CD40 with its ligand CD40L to generate protective T-cell-mediated tumor immunity. Therefore, to create a strategy to target Ads to DCs in vivo, we constructed a bispecific adaptor molecule with the CAR ectodomain linked to the CD40L extracellular domain via a trimerization motif (CFm40L). By targeting Ad to CD40 with the use of CFm40L, we enhanced both transduction and maturation of cultured bone marrow-derived DCs. Moreover, we improved transduction efficiency of DCs in lymph node and splenic cell suspensions in vitro and in skin and vaccination site-draining lymph nodes in vivo. Furthermore, CD40 targeting improved the induction of specific CD8+T cells along with therapeutic efficacy in a mouse model of melanoma. Taken together, our findings support the use of CD40-targeted Ad vectors encoding full-length TAA for in vivo targeting of DCs and high-efficacy induction of antitumor immunity. [ABSTRACT FROM AUTHOR]

Abstract: Adenovirus (Ad)-based vaccines are considered for cancer immunotherapy, yet, detailed knowledge on their mechanism of action and optimal delivery route for anti-tumor efficacy is lacking. Here, we compared the anti-tumor efficacy of an Ad-based melanoma vaccine after intradermal, intravenous, intranasal or intraperitoneal delivery in the B16F10 melanoma model. The intradermal route induced superior systemic anti-melanoma immunity which was MyD88 signaling-dependent. Predominant transduction of non-professional antigen-presenting cells at the dermal vaccination sites and draining lymph nodes, suggested a role for cross-presentation, which was confirmed in vitro. We conclude that the dermis provides an optimal route of entry for Ad-based vaccines for high-efficacy systemic anti-tumor immunization and that this immunization likely involves cross-priming events in the draining lymph nodes. [Copyright &y& Elsevier]

Conditionally replicating adenoviruses (CRAds) were developed as new tools for cancer therapy. CRAds specifically replicate in and kill cancer cells. Within a solid tumor mass, release of newly formed infectious particles from infected cancer cells allows additional cell layers to be infected and destroyed. When used as monotherapeutic agents, CRAds showed only limited effects in clinical trials. Combination studies consisting of CRAd virotherapy with chemo-, radio-or enzyme prodrug therapy, however, showed additive or even synergistic effects and encouraging results in clinical studies. Furthermore, increased CRAd efficacy could be achieved in preclinical models by targeting CRAd infection specifically to tumor cells or via insertion of therapeutic genes in the CRAd genome. In this review, different mechanisms to achieve CRAd specificity, the efficacy of CRAds in clinical trials and ways to enhance their oncolytic potency are discussed. [ABSTRACT FROM AUTHOR]