Scientists at NSU have proven that a new oncolytic virus with an integrated immunostimulatory gene and an additional mutation destroys cancer cells and causes almost no harm to healthy ones

The study of the properties of an oncolytic virus, created based on adenovirus serotype 6, modified by inserting an immunostimulatory gene, is conducted by a first-year graduate student, an engineer of the new biomedical technologies laboratory.Faculty of Natural Sciences of Novosibirsk State University (FSN NSU) Anastasia Pak. She conducts this work together with a junior research associate of the laboratoryDarya Zabelinaunder the scientific guidance of Doctor of Biological Sciences, Professor, Academician of the Russian Academy of Sciences, chief researcher of the laboratory of biomedical technologies FEN NSUSergei Netesov.

—We began the study of the properties of our genetically modified oncolytic virus with proof of the correctness of the transgene insertion conducted by us. In this process, we carried out a preliminary assessment of the expression of this integrated gene and the protein encoded by it, which belongs to the interferon family, in human lung adenocarcinoma cell lines infected with this virus. We established that our transgene is indeed correctly inserted into the adenovirus, and we detect the presence of its mRNA and the immunomodulatory protein itself in cancer cells infected with our oncolytic virus.Next, we tested its cytotoxicity (that is, the ability to destroy living cells of an organism, causing their death) and compared it with that of the “wild” (i.e., unmodified) type of the same virus., — Anastasia Pak said.

In the experiment, the gene-modified variant of adenovirus on the healthy cell line proved to be significantly less cytotoxic than the “wild” type, while no difference in this indicator was observed on the cancer cell line — both viruses were found to be equally capable of destroying the affected cells. Thus, the selectivity of the virus was demonstrated, that is, its ability to selectively affect the tumor while leaving healthy tissues intact.

—The results of the conducted studies indicate that we managed to engineer an oncolytic virus that infects only tumor cells and almost does not harm healthy ones. Such a virus does not occur in nature — it can only be obtained under laboratory conditions.— explained Anastasia Pak.

So far, studies have been conducted in vitro — on cell lines. Fibroblasts (the main cells of connective tissue) and keratinocytes (the main cells of the epidermis) of humans were used as healthy cells, and as pathological — cell lines of human lung adenocarcinoma. In the second half of the current year, it is planned to conduct a study of an oncolytic virus in synergy with chemoimmunotherapy on cell lines.

Currently, oncolytic drugs based on viruses are being developed and are beginning to be introduced into clinical practice in many countries.

—Healthy cells, when infected by a virus, produce and release antiviral proteins and interferons. They make neighboring cells resistant to viral infection. In a tumor, everything is arranged differently — it is a chaotic accumulation of cells that weakly interact with each other. For this reason, viral particles entering the tissue from the bloodstream can easily accumulate. The situation is aggravated by the fact that cells in the tumor often do not have functioning antiviral defense mechanisms and do not produce interferons.It is precisely in the host cell that conditions are created, optimal for virus reproduction, as a result of intensive division and other processes, favoring viral replication,— said Anastasia Pak.

As explained by the graduate student, it has been established in recent years that upon exposure to tumor cells, oncolytic viruses do not limit themselves to destruction. This process releases tumor antigens and “turns on” danger factors, as a result of which immune system cells are activated and begin to attack the tumor. Importantly, the oncolytic virus also activates other molecules, including anti-inflammatory cytokines, which makes the antitumor response so powerful that it can destroy not only the primary tumor focus introduced by injection but also metastases in the body.