Oncolytic viruses at a new stage
Maxim Russo, " <url>"
In April of this year, about three hundred scientists gathered at the International Conference on Oncolytic Viruses (International Oncolytic Virus Conference) in Oxford. In the early 2000s, when these conferences were established, they gathered only about sixty people. "These were very small meetings of crazy people working with viruses," says molecular biologist Jean–Simon Diallo from the Ottawa Hospital Research Institute. "Now we've really seen a shift."
The shift is also visible in the activity of large pharmaceutical corporations. In February, Merck allocated $394 million to buy an Australian company working with viruses that kill tumor cells. It seemed like a huge sum at the time. But already on May 2, the record was blocked by another pharmaceutical giant. Johnson & Johnson has announced that it will spend up to one billion dollars on the acquisition of a company developing oncolytic viruses.
Doctors began to notice a decrease in some types of tumors after a patient was infected with a virus at the beginning of the XX century. The first description of a tumor-destroying virus as a deliberately used method of therapy is contained in the 1951 novel "Dragon Island" by American science fiction writer Jack Williamson (the term "genetic engineering" first appeared in the same work). But already in the 1960s, not fictional writers, but real doctors began to experiment with viruses that could help fight tumors. However, there was no genetic engineering at that time, so scientists could not create modified viruses at will and were forced to look for suitable candidates among natural viruses. Polio virus, adenoviruses, Coxsackie viruses, echoviruses claimed this role. But the use of natural viruses was a complicated matter and did not guarantee success. Sometimes an uncontrolled infection developed, dangerous for the patient's life. In other cases, the body's powerful immune response suppressed the virus and prevented it from dealing with the tumor. As a result, oncolytic viruses could not compete with chemotherapy and radiation therapy either in terms of cost or effectiveness.
One of the few methods of tumor virotherapy approved for clinical use was RIGVIR (ECHO-7), created under the leadership of Aina Muciniece in Latvia. In her research of the 1960s- 1970s at the Kirkhinstein Institute of Microbiology of the Latvian Academy of Sciences, Aina Muciniece identified a variety of echoviruses that did not cause a dangerous infection, but had an oncolytic effect. In 2004, the State Agency of Medicines of Latvia officially registered the drug RIGVIR for the treatment of melanoma. But many oncologists point out that until now, during clinical trials, there has not been enough convincing evidence of its effectiveness. Moreover, the drug manufacturers are accused of unethical advertising, and an American oncologist David Gorsky bluntly calls RIGVIR production quackery. At the beginning of 2017, the Association of Oncologists, the Association of Chemotherapists and the Association of Rare Diseases of Latvia, as well as the Faculty of Pharmacy of Riga Stradyn University appealed to the Ministry of Health of Latvia and the Medicines Agency with a request to exclude RIGVIR from the list of medicines compensated by the state, since its effectiveness has not been proven. But the Ministry of Health replied that RIGVIR will remain on the list of medicines and that it assesses the risk-benefit ratio when using it as acceptable.
Nowadays, the ability to modify the viral genome has given specialists in tumor virotherapy fundamentally new opportunities. Although it is still much cheaper to use chemotherapy, there are already areas of oncology where virotherapy potentially has advantages. First of all, this is the treatment of brain tumors. As you know, the body has a hemato-encephalic barrier – a system that prevents the penetration of various pathogens from the blood into the brain. But this barrier also prevents drugs aimed at treating tumors from reaching brain cells, and among viruses there are those who are not afraid of the hemato-encephalic barrier. Therefore, it is the treatment of brain tumors that is now the most promising direction in the development of oncolytic viruses.
The current surge in interest in oncolytic viruses is associated with serious achievements in recent years. The largest of them was the official registration by the US Food and Drug Administration (FDA) of genetically modified herpes T-VEC (commercial name Imlygic) as a drug for the treatment of melanoma. The T-VEC virus (Talimogene laherparepvec) is based on the herpes virus of the first type (HSV-1). The ICP34.5 gene has been removed by genetic engineering methods, which allows the virus to infect only tumor cells and deprives it of the ability to penetrate into healthy cells of the body. A human gene responsible for the production of the cytokine GM-CSF, a protein that stimulates the immune response, is also inserted into the genome of the virus. Therefore, T-VEC not only infects and destroys tumor cells itself, but also helps the immune system fight them. More about this method of treatment is described in the special essays "Herpes virus fights cancer" and "Double blow to the tumor".
True, in the largest clinical trial, Imlygic did not show a statistically significant increase in patient survival compared to other drugs, but the results they showed were enough for a positive decision by the FDA. In addition, the tests proved that Imlygic fights not only the tumor where the drug was injected, but also tumors in other parts of the body.
Several more methods of viral therapy are on the way. Duke University has already passed the first trials on patients of a modified polio virus as a means of combating a brain tumor – glioblastoma. The rabies virus, which spreads through the nervous system, is also being tried to adapt for the passage of the hemato-encephalic barrier and the treatment of brain tumors. But here, so far, experiments are being conducted on laboratory mice.
An important achievement was the evidence obtained mainly in animal studies that oncolytic viruses are especially effective in combination with another method of therapy – the use of checkpoint inhibitors that stimulate the immune response of the tumor. Immune checkpoint inhibitors are special molecules secreted by tumors to protect themselves from the immune system. By inhibiting them, that is, stopping their action, scientists activate the body's defense.
In a 2017 clinical trial involving 21 patients with late-stage melanoma, Imlygic, together with a checkpoint inhibitor called pembrolizumab, caused a significant reduction in tumors in 13 participants and completely destroyed them in seven.
Jean-Simon Diallo associates a new stage in the development of viral cancer therapy with checkpoint inhibitors. However, when scientists tried to combine checkpoint inhibitors with other therapies, they did not always succeed. Some combinations, which were theoretically expected to be highly effective, did not show encouraging results during clinical trials. This can also happen in combination of checkpoint inhibitors with oncolytic viruses. But so far, most researchers share cautious optimism about the prospects of such a method.
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