Gene-targeted Oncolytic Adenovirus Therapy Plays A Role as A New Star in Cancer Treatment

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and the third leading cause of cancer deaths. Even though significant progress has been made in standard therapies (such as surgical resection, chemotherapy, and radiation therapy), the results are still disappointing. Therefore, it is necessary to find a new treatment method. There is a brand new field in the field of cancer targeted therapy. Gene-targeted oncolytic virus therapy (GTOVT) is considered to be a promising treatment for HCC. Oncolytic viruses can infect and kill cancer cells without harming normal cells.

The anticancer efficacy of oncolytic adenovirus mainly depends on the host's immune response. As for pathogens, adenovirus triggers a powerful host immune response after infection. This immune response is considered a "double-edged sword" because the oncolytic adenovirus stimulates both antiviral and antitumor immune responses. On the one hand, the host's antiviral immune response should be reduced to ensure that the oncolytic virus has the effect of killing cancer. On the other hand, the anti-cancer immune response caused by oncolytic adenovirus extends its anti-cancer efficacy, including the metastatic side. In order to obtain the maximum cancer killing effect, GTOVT must be genetically or non-genetically modified to construct an oncolytic adenovirus to reduce immunogenicity and equip immunostimulatory molecules.

Cancer selectivity is an indispensable function of oncolytic adenovirus, which can ensure effective anti-cancer efficacy while avoiding adverse side effects. Several studies have reported that tumor selectivity can be achieved by deleting some viral genes. For example, the reverse region 2 (CR2) of the protein encoded by the adenovirus E1A gene replaces the RB and RB-related proteins of the E2F transcription family in infected cells, thus enabling the transformation of quiescent cells entering the S phase. This process is essential for virus replication in normal cells.

In addition to cancer selectivity, oncolytic adenovirus also has another essential function, that is, it has a strong effect of killing cancer cells. As mentioned above, adenovirus has sufficient genomic capacity for therapeutic gene vectors. In addition, more and more studies have reported that oncolytic adenoviruses can infect and express foreign functional genes without target cells. Function/effector genes can be classified by their functions in four categories: (1) tumor suppressor genes; (2) cytotoxic genes; (3) immunomodulatory genes; (4) tumor antigens.

Despite its growing advantages, gene-targeted oncolytic virus therapy has not yet become popular. This is because current research has found that gene monotherapy based on oncolytic adenovirus is not sufficient to eradicate tumors. The limited antitumor efficacy of oncolytic adenovirus is due to several reasons. First of all, most people have immunity against adenovirus. By quickly clearing the virus after systemic administration, the efficacy of oncolytic adenovirus is significantly hindered. Second, the virus-mediated inflammatory response may cause serious complications and compromise safety. Third, viral antigens may be presented by target cells after viral transfection and eventually induce cytotoxic cell responses. In short, the host immune response triggered by adenovirus is one of the determinants of its anti-cancer efficacy.

In terms of virus-mediated immune responses, they include host antiviral and anti-tumor immune responses. Virus-based immunotherapy is the delivery of viral vectors with immunostimulatory factors to reduce the antiviral immune response and enhance the antitumor immunity in the tumor environment.

Due to the advantages of oncolytic adenovirus, many preclinical studies on HCC treatment have been carried out. Gene-targeted Oncolytic Viral Therapy (GTOVT) has innovated a brand-new field of cancer treatment. By designing viral vectors, it can target all cancer types. Due to several good properties, adenovirus is the most promising drug for GTOVT. In theory, genetically armed viral vectors can target all types of cancer, including solid tumors and hematological malignancies. Although the clinical safety of viral preparations has been confirmed through clinical trials, oncolytic adenovirus has not been used in clinical practice. This is because the oncolytic adenovirus is strictly inhibited during systemic delivery in the body, which affects its effectiveness. In order to overcome this shortcoming, bioengineering, molecular and immunological methods have been considered.

For example, modified oncolytic adenoviral vectors are produced through genetic and/or non-genetic tools to avoid neutralization by antiviral antigens and serum components and prevent MPS from segregation in the liver and spleen, which is another major reason for removing viruses from the circulation. In addition, the high interstitial pressure and compact extracellular matrix (ECM) prevent the virus from spreading to the tumor. These problems can be partially solved by equipping lysosomal adenovirus with functional genes (such as hyaluronidase or metalloprotease), or using MSC as a viral vector to induce viral uptake.

Therefore, immunotherapy based on oncolytic Ad has recently attracted increasing interest due to its ability to regulate anti-tumor immune responses and evade anti-viral immune responses. However, finding a balance between anti-tumor immune response and anti-viral immune response is a key issue that has not yet been resolved.

https://www.creative-biogene.com/Services/Custom-Viral-Service/Oncolytic-Virus-service.html

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