An interest in the practical application of viruses in oncology already emerged in the mid-19th century, when it was observed that terminally ill cancer patients experienced a regression in their tumours when suffering from an acute infection. The majority of these cases were observed in young patients with leukaemia and lymphomas. Although the remission was short-lived – one or two months – and a complete cure was never documented, the fact that any remission was observed was intriguing enough to inspire further study. At the time, mankind had not yet even discovered the existence of viruses.
The first official reports of cases of spontaneous tumour regression were recorded at the beginning of the 20th century after patients were given Pasteur vaccinations (a weakened rabies virus). However, by coincidence Paul Ehrlich had discovered at the same time that certain diseases, including malignant tumours, could be treated with chemical agents, while Japanese pathologists Yamagiwa Katsusaburō and Kōichi Ichikawa proved that it was possible to induce cancer in laboratory animals using chemical agents laying the foundations of chemical carcinogenesis. These discoveries opened the flood gates for an avalanche of research in both of these directions (chemical carcinogenesis and tumour chemotherapy) and the concept of tumour virology was pushed aside.
In 1922, a Romanian pathologist, cytologist and immunologist named Constantin Levaditi and his colleagues at the Pasteur Institute observed that the smallpox virus had a particular affinity for cancer cells (oncotropism) and was also capable of destroying them (oncolysis). This inspired extensive studies of other potentially oncotropic (attracted to cancer cells) and oncolytic (capable of destroying cancer cells) viruses in the 1940s.
In the middle of the 20th century it became possible to propagate viruses outside the body in human cell lines. This created new research possibilities. However, further interest in virotherapy varied from excitement and exuberance in the 1950s and 1960s to nearly complete denial in the 1970s and 1980s, because the mechanisms of viral activity were still unclear, the pathogenesis (how a disease is created) question still hadn’t been answered and support for chemotherapy only grew, as did public interest in other significant viruses including HIV.
Interest in virotherapy was renewed at the beginning of the 21st century due to new possibilities in gene engineering. It became possible to transform defects, so to speak, into positive effects by reducing or completely eliminating pathogenesis and by improving oncotropic and oncolytic properties. Before genetic modification or transformation, viruses were adapted for replication (to ensure reproduction as viruses are parasites of living cells) in specific tissues, infecting them repeatedly with the respective culture. The possibility of genetically modifying viruses marked the modern transition to oncolytic virotherapy, but this didn’t necessarily preclude the use of naturally-occurring viruses. Currently, three oncolytic viruses have been registered – Rigvir® (2004: a natural enterovirus that hasn’t been genetically modified), Oncorine® (2005: a genetically modified adenovirus) and Imlygec® (2015: a genetically modified herpes virus), but a wide range of other viruses are waiting to be approved for clinical practice.
Therefore, oncolytic virotherapy is neither an alternative, nor a traditional treatment method, but rather a cancer treatment that is developing rapidly and that is believed to have the potential to make a significant contribution to cancer treatment overall.
In the late 1950s, Latvia was one of the first Soviet republics to administer polio vaccinations to at-risk members of the population with injections of inactivated poliovirus vaccines (the Jonas Salk vaccine). Later, vaccination of the population was continued en masse with the oral Albert Sabin vaccine, which contained weakened live polio virus.
At the beginning of the 1960s, the scientists at the A. Kirhenšteins Microbiology Institute decided to study how the microflora in the intestines of pre-schoolers change before and after receiving oral polio vaccinations. It turned out that the vaccine had no significant effect on the microbiome (all of the microorganisms living within the intestines) of the vaccinated children, but the scientists were intrigued by the number of enteroviruses living there. As a lucky coincidence, the Cancer Virotherapy Laboratory was created by professor Aina Muceniece in 1965, whose aim was to study a number of potentially oncotropic and oncolytic enteroviruses, which was a popular field of research at the time throughout the world.
Enteroviruses belong to the Picornaviridae family of viruses and they are among the smallest RNA viruses known. These include poliovirus, rhinovirus, coxsackievirus and ECHO viruses. Of all of the viruses studied, the ECHO group of viruses (ECHO6, ECHO7, ECHO11 and others) displayed the most oncotropic and oncolytic characteristics. By studying their potential use as an oncolytic virotherapy, professor A. Muceniece discovered that 70% of human enteroviruses displayed oncotropic and oncolytic characteristics in human angiosarcomas (malignant blood vessel tumours) and chondrosarcomas (malignant cartilage tumours) that were heterotransplanted (when tissues of one species are transplanted into a different species) into the cheek pouches of Siberian hamsters. In vitro experiments confirmed that the majority of human tumours absorb human enteroviruses. However, the range of enteroviruses absorbed by the human tumours was dependent on the type of tumour.
Since there were no effective melanoma treatments in the second half of the 20th century, scientists began adapting the ECHO-7 virus to melanoma tissues, which had a positive effect that served as the basis for the 2002 patent of the Rigvir® (named after the city in which it was studied) strain gained in 1968. A series of fortuitous coincidences and the wisdom of local researchers colluded to allow certain viruses to present themselves to Latvian researchers in the distant 1960s of which Finnish colleagues would write 50 years later: “enteroviruses are a promising tool in treating cancer.”
Oncotropism un oncolysis
Certain viruses have the ability to enter and replicate themselves in cancer cells. Although oncolytic viruses are equally capable of entering both cancerous and healthy cells, the pathologically altered signal transduction of tumour cells, their response to stress and homeostasis make them especially suited to viral replication. It’s possible that the typical antiviral activity of cells, which enables them to recognise and eliminate them, is somehow changed in tumour cells, which enables the targeted replication of the virus in this specific environment. Today, for example, it’s known that reoviruses prefer to occupy those cancer cells upon which the mutated Ras antigen is found. This provides a rational justification for the belief that reoviruses could be applied to tumours with the Ras mutation. However, it turns out that a virus’s preference for cells in which to replicate is much more complex and depends on the delicate interaction between the virus and the tumour as well as the state of the body’s immune system. This can be affected by cell surface receptors, the potential of the virus to replicate and cellular antiviral response elements. The destructive (lytic) potential of oncolytic viruses on tumours depends on the virus itself, the virus’s natural or induced tropism and the susceptibility of the tumour cells to a variety of cell deaths (apoptosis, necrosis, pyroptosis and autophagy).
Cell surface receptors, which are selectively recognised by different viruses, can differ for a variety of tumours. For example, the protein that attracts polio viruses is usually found on well-differentiated glioma (a type of brain tumour) cells. By contrast, vesicular stomatitis virus (VSIV) is almost pantropic because it binds to a specific receptor that is ubiquitous. However, the tropism of a virus also depends on the hospitality of a specific tumour. A virus will replicate selectively only in those cells that contain specific defective pathogenesis pathways.
Over the course of evolution, viruses have also adapted to the changing rules of the human body. Therefore, it’s unlikely that a miracle virus will be discovered that is equally effective in the treatment of all tumours. It’s more probable that viruses with differing cell capture tactics will be used on the weak points of specific tumour cells. In addition, it should be noted that cancerous tissues are heterogenous and can be comprised of different cells, which can be susceptible or immune to viruses.
Manipulating the virus genome could strengthen the destructive capabilities of oncolytic viruses on tumour cells. It may be possible to increase the capacity of already genetically-modified oncolytic viruses by arming them with new genes that can supress the growth of tumours or stimulate the immune response against tumours.
Oncolytic viruses can also induce autophagy (the self-consumption of the cell) in cancer cells – an essential catabolic process to ensure cell homeostasis. Oncolytic viruses disrupt the complex machinery of cell autophagy to promote their own replication. Finally, some oncolytic viruses are also capable of destroying tumours indirectly by blocking tumour vascularisation.