Nowadays using virus immunotherapy remains challenging mainly because of the lack of tumor specificity. However, using genetic engineered viruses, there are wide range of possibilities to increase viral-specific tropism. In this study published by the group of Zhen Xie at the National Research Center for Information Science and Technology at the Tsinghua University in Beijing, China, the key concept is the synthetic gene circuits that the authors create which enhance viral immunotherapy avoiding the development of targetable tumor antigens extremely necessary in the environment of immunotherapeutic antibodies.
The role of immunomodulators is to overcome immunosuppression in tumor microenvironment. Systemic administration (like intravenously) of immunomodulators either alone or in combinations cause side effects., which has less side effects than a systemic administration. Adenovirus are oncolytic viruses (OV) with low pathogenic risk, high genome stability, wide range of tissue tropism and a relatively DNA loading capacity. They can be genetically modified and have a high capacity to introduce recombinant genes in their genome.
The genetic modification of the virus contains the cancer-specific promoters and microRNA inputs that control the adenoviral replication and the expression of immune effectors such as the colony stimulating factor of granulocytes and macrophages (GM-CSF), IL-2 or recombinant genes that express fragments of antibodies that antagonize PD-1 and PDL-1 (receptor and its ligand that downregulates the immune response of lymphocytes T). This new strategy guaranties the expression of the viral driven factors inside the tumor. The expression of these recombinant elements is repressed in a normal tissue, which attenuates the deleterious and the toxic effects of the therapy.
Results indicate that some of the engineered adenovirus can target and impede tumors with high specificity, but only in case of immune-competent mice. To test whether survived mice obtained vaccination against HCC cells after oncolytic virotherapy, cancer cells were transplanted site away from the initial treatment and the result was that all survived mice rejected the second challenge of cancer cells, this suggest that there is an immunological memory. Also, it was observed that lymphocytes in tumors treated with OVs were more abundant than in no treated.
Finally, in my opinion I think that their applicability is limited in several ways because viral vectors could trigger a host anti-virus immune response, for example antibodies could neutralize structural components of viral vectors; or if they were administered intravenously, our phagocytic system would rapidly eliminate the virus in the liver or spleen. However, I think it still have an incredible potential because all these problems could be solved by different modifications such as covering the capsid with polymers in order to inhibit immunogenic effectors cells or making modifications in the fibers of the virus. Finding the balance between the anti-tumor immune response and anti-virus immune response is essential to future viral therapies.
Bibliography: https://www.ncbi.nlm.nih.gov/pubmed/31641136
Vicent Tur Planells. Microbiology course. 2º year of Biotechnology.
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