Anatomical and physical barriers to tumor targeting with oncolytic adenoviruses in vivo.

Despite promising results in preclinical studies, the therapeutic efficacy of oncolytic adenoviruses (Ads) has not been reproduced in clinical trials in patients with cancer. Recent studies have identified several obstacles that limit the therapeutic efficacy of oncolytic Ads. These obstacles include the lack of a primary Ad attachment receptor on tumor cells in situ, as well as innate host defense mechanisms that recognize Ads as pathogens and act to facilitate their elimination. This review focuses on anatomical barriers inside solid tumors that limit Ad transduction, and specifically barriers associated with several factors: (i) the mechanisms of tumor vascularization and the metabolic microenvironment; (ii) the tumor stroma, which tightly surrounds nests of malignant cells; and (iii) the epithelial phenotype of cancer cells, particularly the trapping of viral receptors in tight and adherens junctions. Potential strategies to overcome these obstacles are also presented. Because published data on the physical barriers to Ad transduction of tumors in situ are limited, studies with other macromolecules used in tumor therapy are also discussed.