Oncolytic virotherapy
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Oncolytic virotherapy is a treatment method that involves the use of viruses to destroy the tumor and stimulate a systemic antitumor immune response. This is one of the most promising and dynamically developing areas of oncology. Over the past 30 years, more than 200 clinical trials of drugs for viral cancer therapy have been conducted in the USA alone. Virus-based cancer drugs are also being developed in other developed countries, including Germany.
Content
- When was oncolytic virotherapy first used?
- Newcastle disease virus
- How does the NDV oncolytic virus work?
- For what cancers can NDV be used?
- Dendritic cells plus an oncolytic virus
- What other viruses can be used for cancer virotherapy?
- What is holding back the widespread use of virotherapy?
- Where can you undergo virotherapy?
When was oncolytic virotherapy first used?
The world's first drugs approved for clinical use were Oncorine and Gendicine. They were developed and began to be used in China in 2007, but they are not widely used around the world.
Most experts therefore consider 2015 to be the year when virus therapy was excluded from the category of experimental treatment methods. In that year, the FDA approved Imligic for melanoma treatment for use in the USA. Since 2016, it has been applied in other developed countries.
The development and clinical research of many other viruses that destroy cancerous tumors are ongoing. Most of the research is carried out in the USA, Japan, Germany, Finland, and China.
Newcastle disease virus
At the IOZK Medical Center (Cologne, Germany), doctors successfully use a drug based on the Newcastle disease virus (NDV). It is an avian paramyxovirus-1, which is harmless to humans.
Antitumor agents based on this virus began to be developed back in the 1960s of the twentieth century. At that time, the virus had not yet been introduced into the human body, but with its help, an oncolysate was created. These are fragments of a destroyed malignant tumor that were used to stimulate the immune response.
In 1971, Csatary described a unique clinical case: in a farmer with aggressive colon cancer, the tumor suddenly disappeared along with all its metastases. The author of the publication suggested that this was not a miracle at all, but the result of an accidental infection of the patient with NDV from birds. The tumor began to regress just after an outbreak of Newcastle disease on his farm. As a result, interest in this virus on the part of scientists increased sharply, which led to the development of drugs for cancer treatment.
How does the NDV oncolytic virus work?
NDV virotherapy works through the following two mechanisms:
- Infection of a malignant tumor and destruction of cancerous cells due to a direct cytopathic effect
- Induction of an antitumor immune response
Once introduced into the human body, the virus attacks only tumor cells and destroys them. Healthy tissues are, therefore, not affected. What is the reason? Why does this virus "hate" cancer so much?
The selective effect can be explained by the structural features of cancer cells. Their surface contains too many glycoproteins rich in sialic acid. It is this that becomes the target for the virus: NDV destroys sialic acid, thereby destroying the cancer cell.
Interestingly, the virus has a stronger effect on more aggressive tumors. This is due to the fact that the amount of sialic acid determines the tumor's ability to spread metastasis. Overexpression of sialic acid creates a negative charge on the membrane. It provokes intercellular "shocks", thereby pushing cancer cells into the bloodstream.
The second mechanism of action of the oncolytic virus is to enhance antitumor immunity. How does it work? First, as a foreign agent, NDV itself enhances the activation of the immune system. Second, sialic acid, found in cancer cells, plays a role in immune evasion. Under its thick "layer" are hidden antigens that go unnoticed by the immune system. After the introduction of the virus, these antigens become "naked". Immune cells recognize them, so the enhancement of the systemic antitumor immune response occurs.
For what cancers can NDV be used?
Doctors are trying to use virotherapy for the treatment of many oncological diseases. Dozens of studies have been completed, are ongoing, or are planned to evaluate the efficiency of NDV for a variety of tumors. Some of them showed good results, for example:
- Glioblastoma: introduction of the virus allowed for the long-term survival of patients with an aggressive brain tumor (pilot research by Steiner H.H. et al.)
- Head and neck tumors: improvement of patient survival rates (Herold-Mende C.)
- Melanoma: improvement of patient survival rates (Niu Z.)
- Kidney cancer: an objective response to therapy has been achieved; this means a shrinkage in tumors by more than 30% according to imaging diagnostics (Pecora A.L.)
- Liver cancer: an objective response to treatment was achieved (Wu Y.)
Many more diseases have been successfully treated in experiments on laboratory animals. For example, preclinical research has demonstrated the high efficiency of virotherapy for lung cancer and rectal cancer. These experiments showed that the virus not only destroys the tumor but also develops immunological memory, which protects against the relapse of the disease.
Dendritic cells plus an oncolytic virus
Some hospitals in Germany have started using NDV together with dendritic cells to improve the efficiency of virotherapy. Dendritic cells are antigen-presenting immune cells. Their task is to capture the antigen, "disassemble" it into fragments, and demonstrate it to T cells in order to trigger a cellular immune response. T cells are not able to recognize native (whole) antigens.
Dendritic cells are used in oncology without viruses as well. They are obtained from the patient's blood and treated with tumor antigens, after which specialists stimulate their maturation and then introduce them into the body.
Doctors in Germany combined two treatment methods. NDV and dendritic cells do not simply add up their effects but significantly enhance each other's effects. Oncolytic virus is used as an adjuvant for dendritic cell vaccines because it enhances the immune response. In turn, dendritic cells help viruses better find tumors and attach to cancer cells throughout the body.
The combination of virotherapy and dendritic cell vaccine therapy can be used in two different ways. The first is the sequential introduction of the virus, followed by dendritic cell injections. The second is the infection of dendritic cells by the virus even before its introduction into the body.
We can see the first example of use in Leipzig, Germany. The development of the DeltaVir vaccine is ongoing there. This option of virotherapy has already proven itself to be effective for some tumors. For example, Ilett E.J. described a case of long-term remission in a patient with end-stage prostate cancer and multiple bone metastases.
What other viruses can be used for cancer virotherapy?
Currently, only three viruses are acknowledged as effective and approved for clinical use, that is, they are part of standard cancer treatment in certain countries, such as:
- Oncorine, China
- Rigvir, Latvia
- Imlygic, the USA
But there are also a huge number of viruses that are being researched. Some drugs are already in the final phase of clinical research. These are, for example, Pexa-Vec, Reolysin, PVSRIPO, CAVATAK, and others.
Drugs for virotherapy are created based on the following viruses:
Poxviridae. These are large DNA viruses, some of which may cause diseases in humans. The weakened strains of the vaccinia virus are applied to use the vaccine.
Herpesviridae. These are viruses in the herpes family. There are eight types in total. The peculiarity of the virus is that once it enters the body, it remains there forever. Genetically modified herpes viruses types 1 and 2 are used for the creation of drugs for cancer.
Parvoviridae. Parvoviruses are small DNA viruses without a lipoprotein envelope. One of them has natural oncolytic properties, namely the RA-1 virus. The NS1 protein is involved in the destruction of cancer cells.
Adenoviridae. More than 50 serotypes of adenoviruses are known. They are not used in their natural form but are used by scientists as viral vectors for the development of oncolytic drugs.
Rhabdoviridae. These include 13 genera of RNA viruses that are weakly pathogenic or non-pathogenic to humans. The virus blocks the division of tumor cells and causes their apoptosis. In clinical and preclinical studies, good results have been achieved in the treatment of gliomas, lung cancer, colon cancer, and stomach cancer.
Paramyxoviridae. The measles virus is from this family. Some strains obtained in the laboratory can interact with the CD46 protein, which is very abundant in leukemia cells and in some adenocarcinomas.
Reoviruses. These are recognized as effective against mutations in the KRAS gene. A Canadian phase 2 study showed improved survival rates in patients with metastatic breast cancer when virotherapy was included in the treatment regimen.
What is holding back the widespread use of virotherapy?
The literature describes amazing cases where patients with aggressive tumors, even at advanced stages and with multiple metastases, achieved good results. The disease went into long-term remission, which lasted for years. In some cases, the cancer did not recur even after follow-up for 5-6 years or more.
Although the success of virotherapy has been recognized by scientists, most viruses that destroy cancer cells have not yet been approved for clinical use. Why? This is due to the fact that virotherapy provides such a result only to a minority of patients. If the virus works, the effect is impressive. But much more often, there is no effect at all. For example, recombinant poliovirus turned out to be very effective for glioblastomas. In cases where it was effective, remission in patients lasted more than 1 year. But in 80% of cases, it had no effect at all. Different cancer cells have different sensitivities to viruses, and doctors’ efforts are now aimed at finding out the reasons why some tumors are destroyed while others are resistant to virotherapy. In the future, scientists will be able to predict responses to therapy by using oncolytic viruses in carefully selected patients. But for now, one can only use viruses, counting on luck. Before starting therapy, it is impossible to determine its efficiency.
Other problems of virotherapy are ensuring selective delivery of the virus to tumor foci and an immune reaction against the virus, which destroys it and then prevents it from attacking the tumor after reintroduction into the body. Once all these problems are solved, virus therapy will become a standard treatment method, but for now it is an experimental technique that is being practiced in specialized centers in countries with a high level of development in the healthcare system.
Where can you undergo virotherapy?
If standard treatment methods no longer help you, you can contact one of the specialized centers in Germany to receive virotherapy. Leading hospitals in Germany are already using it. It is a country with a developed healthcare system, so advanced cancer treatments are rapidly being introduced here.
You are welcome to use the Booking Health service to find out the prices for procedures and choose the most suitable hospital for your treatment in Germany. The Booking Health specialists will help you choose the most suitable medical center that uses oncolytic viruses. The Booking Health website shows the current prices for treatment in Germany. If you make your treatment appointment through our service, the prices for medical services will be lower for you compared to the prices when you contact the hospital directly. This is due to the absence of additional fees for foreign patients.
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Authors:
The article was edited by medical experts, board certified doctors Dr. Nadezhda Ivanisova and Dr. Vadim Zhiliuk. For the treatment of the conditions referred to in the article, you must consult a doctor; the information in the article is not intended for self-medication!
Sources:
National Center for Biotechnology
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