Virotherapy is an emerging branch of medicine which explores the use of viruses to kill cancers. Oncolytic virotherapy means the elimination of malignant cells by viral propagation inside the tumor. The biological basis of this phenomenon is virus tropism, which means that different viruses have selective preferences for particular cells.
This results in the differences in disease manifestation from virus to virus. Most viruses in nature have a tropism for malignant cells, which makes them suitable for oncolysis. Oncolytic viruses include oncolytic measles virus, oncolytic vaccinia viruses, oncolytic HSV, reovirus and so on. In some trials, oncolytic viruses have been combined with chemotherapy or radiation.
Normal antiviral responses
The body normally responds to viral infection by slowing or stopping cell metabolism, so as to prevent virus replication, and entering apoptosis, or programmed cell death. Tumor cells, however, resist apoptosis, and do not suppress protein synthesis following viral infection, making them more susceptible to damage and death.
This is the basis of oncolytic virus therapy. Even attenuated viruses can propagate inside tumor cells, where they could not inside a normal cell. However, the immune responses in most cancer cells are only partially inactivated, so most tumors show only limited sensitivity to viral infection.
To overcome this, researchers encode virulence factors which are complementary to each other, or which originate from competing virus strains. At the same time, they need to build in protection for normal cells against viral infection.
Mechanisms of oncolysis in virotherapy
The viruses used in oncolysis must be capable of replication, and selective infection of tumor cells. Oncolytic viruses use many means to kill cancer cells, either directly, or through immune mechanisms which destroy the infected tumor cells.
Normally, viruses utilize cell destructive processes like autophagy, apoptosis or necrosis, but only after they have fully used up all cell resources to replicate themselves. In addition, viruses destroy uninfected cells as well, through indirect means, such as disrupting the blood supply to the area, amplifying the existing immune responses against the cancer to make them more powerful, and through specific actions by genetically engineered viruses on the cancer cells.
The viremic threshold
The two important areas of research into oncolytic viruses concern virus delivery to the tumor, and spread of the virus through the tumor. It is known that effective virus delivery involves the so-called ‘viremic threshold’ dose which needs to be exceeded.
The safety record of oncolytic virotherapy is good so far. The greatest challenge in virotherapy, however, is making sure that viruses reach the tumor in sufficient doses to extravasate from blood vessels into the tumor, replicate in tumor cells to create infectious centers, which then expand outwards and merge to destroy the tumor, or perform effective tumor debulking. The doses of virus used for injection are constantly increasing. The injected dose of viruses must be therefore cross the threshold dose.
The major obstacles to this quest are:
- Sequestration of virus in the liver and spleen, which may be overcome by saturating the mononuclear phagocytic system receptors.
- Neutralization of viruses by serum immune factors.
- The need for viruses to selectively bind to vascular endothelium of the tumor blood vessels.
- The need for highly selective increase in the permeability of tumor vascular endothelium, so as to optimize virus extravasation but avoid systemic inflammation.
The spread of the virus, the number and location of virus-infected cells inside the body can be tracked by monitoring certain inserted genes. These are called reporter genes, and help researchers trace the virus spread repeatedly and in a non-invasive way.
One example is the gene which encodes the thyroidal sodium iodide symporter (NIS), which concentrates radioactive iodide in the form of radioisotopes such as 125I, 123I, 124I and 99mTcO4. It can be inserted and then used to monitor the spread of the virus. This approach has been proved valid with the use of CT/SPECT imaging to follow the spread of the oncolytic virus with inserted NIS.
Newer developments and challenges
Radiovirotherapy is another approach under investigation which uses 131I in the form of NIS expression in a virus genome. This will increase the efficacy of the oncolytic virus therapy by adding the administration of high-energy beta particles into the virus-infected tumor, to the virus infection.
The large size of most viruses forms a physical barrier to cell infection, while their ability to evoke an immune response limits their capacity to infect many cells. However, they can both amplify and prime other forms of host immunity, and thus stimulate a general antiviral immune response in the host. Cell carriers are being developed to overcome the physical size barrier. The use of immunosuppressive drugs is also being researched, to encourage intratumoral spread of the virus.
Challenges exist, since with the diminishing of host immunity, the immune-stimulating power of oncolytic virus therapy is also reduced. Moreover, the need of the situation is to develop tumor models which can accurately reflect what is happening in the human body affected by a tumor which has been infected by an oncolytic virus.