Many viruses have the ability to kill cancer naturally, and companies have been studying engineered viruses to target certain tumor types, such as herpes virus, pox virus, adenovirus, polio virus, etc. Genetically modified viruses can specifically attack and destroy cancer cells, and cause less damage to normal cells.
One of such type of virus is oncolytic virus. Due to the nature of the virus, this therapy can be administered systemically or locally to treat primary and metastatic tumors.
Interestingly, tumors are inherently suitable for attack by oncolytic viruses-when genes such as RAS, TP53, RB1, and PTEN are mutated, the ability of cancer cells to resist viral infection will weaken.
Whether it is a natural oncolytic virus or a modified oncolytic virus, it has cytotoxicity and tropism to tumor tissues, can selectively infect tumor cells and replicate in them, and newly generated virus particles will be released, further infecting surrounding cancer cells.
Not only can it directly kill tumors, but it is also expected to stimulate the body's immune response and enhance anti-tumor effects. In summary, the oncolytic mechanisms of oncolytic viruses have the following characteristics and commonalities:
1.Direct oncolytic effect of virus
2. Activate the anti-tumor immune response
3.Improve the sensitivity of tumor cells to chemoradiotherapy
4. Expression of foreign genes with therapeutic effects
5. Destroy the tumor microenvironment that inhibits the change and directly kill the immunosuppressive cells
In the following part, an overview of preparation of oncolytic virus will be introduced.
The virus is directed to induce evolutionary transformation. Through the use of a large number of randomly generated recombinant precursor viruses, targeted selection produces new virus variants or serotypes specific to tumor cells. A random virus candidate library is obtained by the homologous recombination method, and then a series of pre-designed screening or induction conditions (such as higher tumor specificity or invasion activity, etc.) are used to obtain an oncolytic virus with preliminary targeting, and then Preclinical models or screening conditions were used to further screen for oncolytic viruses with the desired therapeutic properties. Directed evolution was successfully applied to the screening of recombinant adenoviruses, and oncolytic adenoviruses such as ColoAd1, Ad11p, and Ad3 were obtained.
2.Toxic attenuation transformation
Attenuation of virus toxicity. Deletion of one or some virus genes or gene regions through genetic modification technology to eliminate its effect on normal cells and only function in tumor cells, making the virus safer and more tumor-specific. Cancer cells and virus-infected cells will show similar signal pathway changes, especially in some periodic gene regulation. Thymine and ribonucleotide reductase are responsible for DNA synthesis in cells and are expressed only in cells that are actively replicating. These enzymes are also present in the genome of certain viruses (such as HSV, vaccinia) and allow the virus to replicate in resting (non-replicating) cells, so if they are inactivated by mutations, the virus will only replicate in proliferating cells such as cancer cell.
3. Genetic engineering transformation
Oncolytic virus genetic modification includes two directions: transduction targeting and non-transduction targeting.
1) Transduction targeting, this direction involves modifying viral coat proteins to target tumor cells while reducing access to non-tumor cells. This method of selective tumor modification is mainly applied to adenovirus and herpes simplex virus type I (HSV-1).
2) Non-transduction targeting, this direction is mainly to modify the viral genome, put key parts of the viral genome under the control of tumor-specific promoters, so that it can only be replicated or transcribed in cancer cells. Specific promoters should be active in tumors, but inactive in most normal tissues, especially the liver (the liver is the organ most exposed to blood viruses). Many such promoters have been discovered and studied and used in cancer treatment research, such as the hTERT promoter. Similarly, there are differences in the expression of miRNA between healthy tissues and tumors. The use of microRNA (miRNA) artificial target sites or miRNA response elements (MRE) can also regulate virus replication well, so that some oncolytic viruses are only in tumor cells and so on. Experimental research proves that using dual targeting (transduced and non-transduced targeting) has better therapeutic effect and higher safety than using single targeting.