Oncolytic virotherapy has emerged as a novel antitumor strategy, which can induce the lytic death of tumor cells as a result of rapid viral replication. Although many different viruses are used in virotherapy, including adenoviruses (Ads), herpes simplex virus, reovirus, measles virus, and Newcastle disease virus, adenovirus serotype 5 (Ad5) is one of the most commonly used viruses in oncolytic virotherapy. The virotherapy using oncolytic Ad has been widely used in clinical applications because of the high titers, the ability to insert larger size of therapeutic genes, and high transduction efficiency in dividing and non-dividing cells. Importantly, when oncolytic Ad replicates, they do not integrate their genome into the host, therefore oncolytic Ad does not induce mutagenesis related to the oncogene. These unique features give oncolytic Ad potency as gene carriers and increase safety than other oncolytic viruses such as oncolytic lenti-, retro-, and adeno-associated virus.
Figure 1. Schematic diagram of the cancer cell-specific killing of oncolytic Ad. (Choi J W, et al. 2015)
Oncolytic Ads have long been studied and tested in patients with malignancies without severe side effects and some clinical trials are ongoing. For effective oncolytic activity, oncolytic Ads must specifically infect and efficiently replicate within cancer cells. Nevertheless, many cancer cells do not express or downregulate the coxsackie and adenovirus receptor (CAR), leading to decreased transduction of Ad5, which is commonly used for Ad-based vectors. Thus, Ad5 fibers, the capsid moiety responsible for virus-cell surface receptor interaction, have been modified to increase their transduction to cancer cells. An RGD-motif inserted into the fiber knob increases viral interaction with integrins, which are highly expressed on some cancer cells, including ovarian and prostate cancers. Ad5 fiber was also replaced by other serotype fibers to redirect to different receptors.
To achieve tumor selectivity, two main modifications on Ads genome have been applied. The first modification uses small deletions in the key viral genes that are required for replication in normal cells. These small deletions are complement with phenotype alterations in cancer cells, thereby oncolytic Ads replication is limited to tumor cells. Bischoff et al. first used this method and introduced ONYX-15 (dl1520), which lacks a functional E1B55K gene and replicates only in cells with mutations in the p53 gene. Besides, the deletion of other section of the E1B gene, E1B19K, leads to replication-selective oncolytic Ad. The second main modification on the Ads' genome to produce oncolytic Ads is the insertion of tissue- or tumor-specific promoters to control viral replication. Rodriguez et al. first used this approach by insertion of prostate-specific antigen (PSA) promoter for expression of E1A. Other tissue-specific promoters also have been used including α-fetoprotein for liver cancer, tyrosinase for melanoma, and carcinoembryonic antigen (CEA) for colorectal cancer. Similarly, some oncolytic Ads express E1A under the control of the telomerase reverse transcriptase (TERT) promoter against TERT-positive cancer cells.
Recent developments in immunology including the clinical applications of immune-checkpoint inhibitors, have greatly increased the understanding of the interaction between oncolytic virus and host immune system. Studies have suggested that combination therapy with immune checkpoint blockade can then efficiently eliminate the tumors. Moreover, transgenes that promote local cytokine release and tumor infiltration of lymphocytes are often included in the oncolytic adenoviral genome such as, interferon (IFN)-α, granulocyte macrophage colony stimulating factor (GM-CSF), cluster of differentiation 40 ligand (CD40L), and interleukin (IL)-12 and -18. Re-activation of the host anti-tumor immune defence after infection with oncolytic Ads expressing GM-CSF has been established in several preclinical models with multiple adenoviral mutants and in the early phase clinical trials. One of these mutants, replication-selective Ad5/3-∆24-GM-CSF, also called as Oncos-102, has been tested in patients with metastatic solid cancers leading to stable disease or minimal responses in half of the patients. IL-12 is a proinflammatory cytokine that may activate the host anti-tumor immune responses after oncolytic virus infection. IL-12 activates both innate and adaptive immune systems through promoting antigen presentation and has been incorporated in many oncolytic Ads.
Despite remarkable results, the application of oncolytic Ad in cancer therapy is faced with serious challenges. Overexpression of PD-L1 following treatment with oncolytic Ad and IFNγ secretion is one of the challenges, and combining anti-PD-L1 antibody with oncolytic Ad therapy has primarily addressed the issue. Besides, in most solid tumors, due to the presence of extracellular matrix, noncancerous cells in tumor microenvironment such as fibroblasts and neovascular formation, the penetration of the oncolytic Ads into the tumor bulk is hampered. Multiple strategies have been used to overcome this problem including using epithelial junction opener, vasoactive and metalloproteinase. Moreover, adaptive Ads are another resolution to circumvent antiviral immunity. According to this strategy, nonhuman adenoviral vectors have been used as alternative vectors. There are some nonhuman Ad serotypes including canine Ad2 (CAV-2), simian Ads, porcine Ad3, bovine Ad3, murine Ad1, and fowl Ads, which have been used as gene delivery vehicles.
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