Herpes virus against melanoma: details

Alexandra Bruter, <url> 

A new stage in cancer treatment began on October 27, 2015. The FDA considered the clinical trials of genetically modified T-VEC viruses in the treatment of melanoma to be successfully completed (for more information about the test results, see our essay "Herpes virus fights cancer") and granted permission for their widespread use.

The FDA (Food and Drug Administration, the FDA) is a regulatory body, without whose permission it is impossible in the United States to turn a promising scientific development into a medicine available to an ordinary American. The FDA, based on data on preclinical studies, gives (or does not give) permission to start clinical trials. Then analyzes their results at each stage and, if successful, gives permission for free use, although, as a rule, continues to look after the drug. Each subsequent approval of a higher level increases the likelihood of the drug entering the market. Increasing this probability often allows you to get additional funding, and not only for a specific approved project, but also similar ones. Moreover, the FDA is quite an authoritative body, so its decisions can, albeit indirectly, influence the decisions made by scientists in other countries.

The idea of fighting cancer using viruses is not new at all, it has been around for more than a century. And finally, the first registered drug appeared. Both patients and scientists pin certain hopes on him. Until now, for example, such therapy was allowed in China, and some patients went there from their countries in the hope, if not completely cured, then at least prolong their lives. The belief in viral cancer therapy seems to be based on long-observed isolated cases of sudden remission after a viral infection and on some successes of immunotherapy.

Back in the XIX century, doctors sometimes noticed that cancer patients, having picked up an infection, sometimes suddenly recovered. In 1891, a surgeon from New York, William Cowley, tried to inject bacteria into tumors in patients. Scientists tried to inject ordinary viruses into tumors until the middle of the XX century: some patients even recovered, but some died from treatment. At this point, such experiments were stopped for some time.

In fact, of course, there is a reasonable grain in this approach. In an ordinary healthy body, some cells quite often degenerate into malignant ones. But there are many mechanisms that prevent their growth and reproduction. A particularly important role here belongs to the immune system, which recognizes and kills malignant cells. If a malignant cell could grow into a tumor, it means that it managed to deceive the immune system. The immune system is constantly teetering on the edge between "do not touch your own" and "kill your enemies", because there is no one simple way to distinguish your own from others. A huge number of molecular mechanisms work to maintain this delicate balance. When the tumor manages to disguise itself, the balance shifts towards "do not touch". A viral infection is a good way to activate the immune system, make it look better, shift the balance towards "killing".

The problem lies only in the fact that all people are different, and by such crude methods as the introduction of bacteria or wild-type viruses into the tumor, it is impossible to shift the balance predictably by the desired amount. That is why, until recently, attempts at immunotherapy and virus therapy have led to sudden remissions, then to equally sudden deaths. Trials of many promising developments were curtailed due to strong side effects, and even the most promising efficiency was far from ideal.

More fine-tuning of viral tools became available with the advent of molecular genetic methods at the very end of the XX century.

The viral drug T-VEC is already quite different from the usual herpes virus. To begin with, the virus had to be modified so that it infected mainly tumor cells. In fact, even wild-type viruses are more likely to infect cancer cells than healthy ones due to the fact that those have broken defense mechanisms. But by removing the protein involved in the infection of nerve cells from the herpes simplex virus (it is the ingestion of the herpes virus into nerve cells that makes the disease chronic), it was possible to obtain a weakened virus, which, on the one hand, is less dangerous for the patient, on the other hand, is also dangerous for the tumor.

Another deleted gene encodes a protein that helped the herpes virus trick the immune system. One of the important points in the activity of the immune system is the presentation of antigens. Both ordinary cells of the body and some cells of the immune system are engaged in it – with greater efficiency. From time to time, proteins that should be inside the cell are brought to its surface and attached there to special surface molecules. The cells of the immune system inspect these proteins, and if they find a foreign one (for example, a cell is infected with a virus and a viral protein appears on the surface), they kill the cell. After that, it can be eaten and digested by other cells of the immune system, and already present enemy proteins themselves. This further enhances the immune response. The herpes virus has a special protein that is able to suppress the presentation of antigens by infected cells. Since this is a very harmful property for the creation of antitumor viruses, the corresponding gene was removed from the viruses. In addition to the increased presentation of antigens due to the features of the virus device, this led to the fact that the virus began to multiply faster and kill cells more efficiently.

The third and most significant change made was the addition to the virus of a gene encoding GM-CSF (Granulocyte-macrophage colony-stimulating factor) – a protein that attracts the very antigen-presenting cells of the immune system.

Thus, a double blow is inflicted on the tumor. On the one hand, viruses infect tumor cells, and the cells die from this. On the other hand, after cell death, GM-CSF attracts immune system cells presenting antigens to the tumor, they eat up the remains of dead cells and present tumor antigens, thereby activating lymphocytes that kill the remaining tumor cells.

The second part is especially important. At this stage, for the successful operation of the system, viruses are injected directly into the tumor. But in the later stages, when such treatment is just indicated, tumors often have distant metastases that are difficult to detect and often impossible to remove. And activated cells of the immune system themselves can find and destroy cancer cells that have begun independent life in remote corners of the body.

Probably, the ability to kill tumor cells away from the injection site has become an important argument in favor of the fact that the drug really works. During clinical trials, it showed moderate effectiveness (median life expectancy increased by 4 months, five–year survival rate - by about 10%), although, of course, in comparison with other drugs and treatment methods, and not at all with a complete lack of treatment. The absence of serious side effects also speaks in favor of this medicine: most patients experienced symptoms similar to a mild cold after the introduction of viruses.

High safety for a drug of this type, a visible, albeit not the most outstanding, positive effect and the serious condition of patients in the target audience – these are the factors that contributed to the issuance of a permit for the use of the drug. On the other hand, the official status of one of the drugs can, in case of further success, accelerate the development of the entire region. Moreover, there are quite a lot of such promising developments. For example, earlier we talked about a modified polio virus fighting a brain tumor – glioblastoma.

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05.11.2015