Abstract
Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have been preclinically used for the study of genetic disorders. However, the clinical application of Ad vectors including HDAds for genetic disorders has been hampered by an acute toxic response. This characteristic, while disadvantageous for gene replacement therapy, could be strategically advantageous for the activation of an immune response if HDAds were used as an adjunct treatment in cancer. Cancer treatments including immunotherapy are frequently limited by the inhibitory environment produced by both tumors and their stroma, each of which express numerous inhibitory molecules. Hence, multiple inhibitory mechanisms must be overcome for development of anti-tumor immunity. The large coding capacity of HDAds can accommodate multiple immune modulating transgenes that could produce a combined effect to overcome tumor-derived inhibition and ensure intratumoral effector T-cell proliferation and function. In this review, we discuss the potential advantages of HDAds to cancer immunotherapy based on potent host immune responses to Ads.
Highlights
Helper-dependent adenoviral vectors (HDAds) are devoid of all viral-coding sequences, and have the advantage of a large transgene coding capacity and, like other Ad vectors, can efficiently transduce a wide variety of cell types from various species independent of cell cycle [1]
Since HDAds lack all viral genes in their vector DNA, cells transduced with HDAds attenuate elimination due to an adaptive cellular immune response to viral genes remaining in vector DNA, such as that seen in animal models treated with first-generation Ads (FGAds) and second-generation Ads (SGAds) [3] (Figure 1)
Cerullo et al reported that an Onc.Ad bearing CpG dinucleotides enhanced the development of cytotoxic T lymphocytes (CTLs) resulting in an improved anti-tumor response when compared to Onc.Ad lacking these sequences in animal models [24]. These results suggest that the presence of an additional TLR agonist inserted into an Ad vector would enhance the development of anti-tumor immunity. These results suggest that Ad vector components provoke an immune response through pattern recognition receptors (PRRs) (e.g., Toll-Like Receptor 9 (TLR9)) in tumors, contrasted to that seen in WT animals/cells, may not be sufficient for the development of an effective cancer vaccination effect resulting from the inhibitory environment produced by both the tumor and its stroma [9]
Summary
Helper-dependent adenoviral vectors (HDAds) are devoid of all viral-coding sequences, and have the advantage of a large transgene coding capacity and, like other Ad vectors, can efficiently transduce a wide variety of cell types from various species independent of cell cycle [1]. Have shown that mice injected with FGAds induce a stronger adaptive immune response than mice injected with HDAds and immediately eliminate FGAd vector transduced cells in livers of mice [3]. This elimination is partially dependent upon transgenes encoded in Ad vectors [3]. HDAd vectors are not associated with a risk of insertional carcinogenesis Based on these desirable features, HDAds have been extensively studied as a therapeutic gene delivery vehicle for genetic disorders (e.g., Hemophilia A [5,8]). We will discuss how these PRR signaling pathways could contribute to cancer immunotherapy despite limiting gene therapy with Ad-based vectors
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