The oncolytic virus is a virus that exclusively infects and kills cancer cells. Because infected cancer cells are destroyed by oncolysis, they release new viral infection particles or virions to help destroy the remaining tumors. The oncolytic virus is thought to not only cause direct damage to tumor cells, but also to stimulate the host's anti-tumor immune response.
The viral potential as an anti-cancer agent was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. Most oncolytic viruses are currently engineered for tumor selectivity, although there are naturally occurring instances such as reovirus and senecavirus, which result in clinical trials.
The first oncolytic virus approved by the national regulatory agency was genetically unmodified ECHO-7 enterovirus RIGVIR strain, approved in Latvia in 2004 for the treatment of skin melanoma. Then (in 2015 and 2016 respectively) it was also approved in Georgia and Armenia. In 2005 the Chinese company, Shanghai Sunway Biotech enrolled oncolytic adenovirus, a genetically modified adenovirus named H101. It obtained regulatory approval in 2005 from CFDA, for the treatment of head and neck cancer. Talimogene laherparepvec (OncoVex, T-VEC) is the first oncolytic herpes virus (modified herpes simplex virus), approved for use by the US FDA and by EMA in the European Union by 2015 for the treatment of inoperable melanoma. In a joint decision, members of the FDA's Oncology Drug Advisory Committee and the Network Therapy Advisory Committee, Cells and Tissues voted 22-1 to recommend oncolytic immunotherapy approval.
Video Oncolytic virus
History
The association between cancer and viral regression has long been theorized, and case reports of regression are noted in cervical cancer, Burkitt's lymphoma and Hodgkin's lymphoma, after immunization or infection with unrelated viruses emerged early in the 20th century. Efforts to treat cancer through immunization or virotherapy (a deliberate infection with the virus), began in the mid-20th century. Because the technology to create a special virus does not exist, all early efforts were focused on finding a natural oncolytic virus. During the 1960s, promising research involved the use of polio virus, adenovirus, Coxsackie virus, ECHO enterovirus RIGVIR, and others. The initial complication is the case of uncontrolled infection, resulting in significant morbidity and mortality; the development of a very frequent immune response, while not harmful to the patient, destroys the virus and thus prevents it from destroying the cancer. Only certain cancers that can be treated through viroterapi are also recognized from the beginning. Even when the response is visible, this response is incomplete and does not last long. The field of virotherapy was virtually abandoned for a while, because the technology needed to modify the virus did not exist and chemotherapy and radiotherapy technologies enjoyed initial success. However, now that this technology has been developed thoroughly, cancer is still the leading cause of death and there is still a need for new cancer therapies, this sideline therapy is now gaining new attention.
Herpes simplex virus
The herpes simplex virus (HSV) is one of the first viruses adapted to selectively attack cancer cells, as it is well understood, easily manipulated and relatively innocuous under natural conditions (only cause cold sores), which tends to pose fewer risks. The mutant herpes simplex type 1 (HSV-1) virus 1716 does not have both copies of the ICP34.5 gene, and as a result is no longer capable of replicating in differentiated and non-dividing cells but will infect and cause highly efficient lysis in cancer cells, and this has proven to be an effective tumor targeting strategy. In various models of cancer in vivo, HSV1716 virus has induced tumor regression and increased survival time.
In 1996, the first approval was granted in Europe for clinical trials using oncolytic HSV1716 virus. From 1997 to 2003, HSV1716 strains were injected into a patient tumor with glioblastoma multiforme, a highly malignant brain tumor, with no evidence of toxicity or side effects, and some long-term survivors. Other safety trials have used HSV1716 to treat patients with melanoma and squamous cell carcinoma of the head and neck. Since then other studies have shown that the outer layer of the HSV1716 variant can be targeted for certain types of cancer cells, and can be used to send additional genes into cancer cells, such as genes to separate harmless prodrugs in cancer cells to release toxic chemotherapy, or the gene ordered to infect cancer cells to concentrate proteins characterized by radioactive iodine, so that individual cancer cells are killed by microscale radiation as well as by viral induced cell lysis.
Other oncolytic viruses based on HSV have also been developed and are in clinical trials. One that has been approved by the FDA for advanced melanoma is talimogene laherparepvec from Amgen. Oncorine (H101)
The first oncolytic virus approved by the regulating body is a genetically modified adenovirus named H101 by the Shanghai Sunway Biotech. It obtained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer. Sunway's H101 and the very similar Onyx-15 have been engineered to remove viral defense mechanisms that interact with the normal human gene p53 , which is very often dysregulated in cancer cells. In spite of early laboratory labor promises in vivo, these viruses do not specifically infect cancer cells, but they still kill cancer cells in a special way. While the overall survival rate is unknown, short-term response rates are approximately double for H101 plus chemotherapy when compared with chemotherapy alone. It seems to work best when injected directly into the tumor, and when the resulting fever is not suppressed. Systemic therapy (such as by intravenous line infusion) is desirable to treat metastatic disease. Now marketed under the brand name Oncorine.
Maps Oncolytic virus
Action mechanism
Immunotherapy
With advances in cancer immunotherapy such as immune checkpoint inhibitors, increased attention has been given to using oncolytic virus to enhance antitumor immunity. There are two main considerations of the interaction between oncolytic virus and the immune system.
Immunity as an obstacle
The main obstacle to the success of oncolytic virus is the patient's immune system that naturally tries to disable any viruses. This can be a particular problem for intravenous injection, in which the virus must first survive interactions with blood supplementation and neutralizing antibodies. It has been shown that immunosuppression by chemotherapy and inhibition of complementary systems may improve oncolytic viral therapy.
Existing immunity can be partially avoided by using a virus that is not a common human pathogen. However, this does not avoid the formation of the next antibody. However, some studies suggest that pre-immunity against oncolytic virus does not lead to a significant reduction in efficacy.
Alternatively, viral vectors can be coated with polymers such as polyethylene glycol, protects from antibodies, but this also prevents viral layer proteins from attaching to host cells.
Another way to help the oncolytic virus achieve cancer growth after intravenous injection, is to hide it in macrophages (a type of white blood cell). Macrophages automatically migrate to areas of tissue destruction, especially where low oxygen levels, characteristic of cancerous growth, and have been successfully used to deliver oncolytic virus to prostate cancer in animals.
Immunity as ally
Although it raises an obstacle by inactivating the virus, the patient's immune system may also act as an ally against the tumor; The infection attracts the immune system's attention to the tumor and can help to produce useful and long-lasting antitumor immunity. This basically produces a personalized Cancer vaccine.
Many cases of spontaneous cancer forgiveness have been noted, though not fully understood, they are considered possible as a result of a sudden immune response or infection. Efforts to induce this phenomenon have used cancer vaccines (derived from cancer cells or selected cancer antigens), or direct treatment with factors that stimulate immunity in skin cancer. Some oncolytic viruses are highly immunogenic and possibly by tumor infections, leading to an anti-tumor immune response, especially viruses that transmit cytokines or other immune stimulating factors.
The virus selectively infects tumor cells because of a damaged anti-virus response. Imlygic, the attenuated herpes simplex virus, has been genetically engineered to replicate exclusively in tumor cells and to produce a prohibited antigen of the immune response.
Oncolytic behavior of wild-type virus
Virus Vaccinia
Vaccinia virus (VACV) is arguably the most successful live bioterapeutic agent because of its important role in the eradication of smallpox, one of the most deadly diseases in human history. Long before the smallpox eradication campaign was launched, VACV was exploited as a therapeutic agent for cancer treatment. In 1922, Levaditi and Nicolau reported that VACV was able to inhibit the growth of various tumors in mice and rats. This is the first demonstration of virus oncolysis in the laboratory. The virus is then shown to selectively infect and destroy tumor cells with great potential, while saving normal cells, both in cell cultures and in animal models. Because the vaccinia virus has long been recognized as the ideal backbone for vaccines due to its strong antigen presentation capability, it combines well with the natural oncolytic activity as an oncolytic virus for cancer immunotherapy.
vesicular stomatitis virus
The vesicular stomatitis virus (VSV) is a rhabdovirus, composed of 5 genes encoded by negative feelings, single-stranded RNA genome. In nature, VSV infects insects and livestock, where it causes relatively localized and non-lethal diseases. The low pathogenicity of the virus is largely due to its sensitivity to interferon, a group of proteins that are released into the tissues and bloodstream during infection. These molecules activate a genetic anti-virus defense program that protects cells from infection and prevents the spread of the virus. However, in 2000, Stojdl, Lichty et al. shows that defects in this pathway make cancer cells unresponsive to the protective effect of interferon and therefore very sensitive to infection with VSV. Because VSV undergoes a rapid cytolytic replication cycle, infection causes malignant cell death and approximately 1000-fold amplification of the virus within 24 hours. Therefore VSV is particularly suited for therapeutic applications, and some groups have demonstrated that systemically administered VSV can be delivered to tumor sites, where it replicates and induces disease regression, often leading to long-lasting healing. Viral attenuation with Met-51 removal technique of the matrix protein obscures almost all normal tissue infections, while tumor cell replication is unaffected.
Recent research shows that this virus has the potential to cure brain tumors, thanks to its oncolytic properties.
Polio virus
Poliovirus is a natural neuropathogen, making it a clear choice for selective replication of tumors originating from nerve cells. The polio virus has a strand-plus RNA genome, whose translation depends on the internal ribosome entry site (IRES) network within the untranslated 5 'region of the viral genome, which is active in neuronal origin cells and allows the translation of the viral genome indefinitely 5 '. Gromeier et al. (2000) replaced the normal IRES virus with IRES rhinovirus IRES, altering tissue specificity. The resulting PV1 (RIPO) virus is capable of destroying malignant glioma cells selectively, while leaving normal untouched nerve cells.
Reovirus
Reoviruses, acronyms for enteric respiratory orphan viruses, commonly infect the respiratory and mammalian intestinal systems. Most people have been exposed to reovirus as adults; However, infections usually do not produce symptoms. Links to the oncolytic reovirus capabilities were established after being found to breed well in various cancer cell lines and lyse these cells.
Reolysin is a reovirus formulation that is currently in clinical trials for the treatment of various types of cancer.
Senecavirus
Senecavirus, also known as Seneca Valley Virus, is a natural type of picornavirus oncolytic found in 2001 as a tissue culture that contaminates Genetic Therapy, Inc. The initial isolate, SVV-001, is being developed as an anti-cancer therapy by Neotropix, Inc. under the name NTX-010 for cancers with neuroendocrine features including small cell lung cancer and various dense child tumors.
RIGVIR
RIGVIR is a drug approved by the National Agency for Drugs of the Republic of Latvia in 2004. It is a wild type ECHO-7, a member of the echovirus family. The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s. Data used to register drugs in Latvia is insufficient for approval to use them in the US, Europe, or Japan. In 2017 there is no good evidence that RIGVIR is an effective cancer treatment.
Semliki virus Forest
Semliki Forest virus (SFV) is a virus that naturally infects central nervous system cells and causes encephalitis. A form of genetic engineering has been pre-clinically tested as an oncolytic virus against severe glioblastoma type brain tumors. SFV is genetically modified in the order of microRNA targets so that it is replicated only in brain tumor cells rather than in normal brain cells. The modified virus reduces tumor growth and prolongs the survival of rats with brain tumors. The modified virus was also found to efficiently kill human glioblastoma tumor cell lines.
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Maraba virus, which was first identified in Brazil's stomach, is being clinically tested.
Engineering oncolytic virus
Directed evolution
The innovative approach to drug development called "directional evolution" involves the creation of new viral variants or serotypes that are specifically directed against tumor cells through rotation of selection directed using large populations of recombinant recombinant precursor viruses. The increased biodiversity generated by the initial homologous recombination step provides a large random collection of viral candidates which can then be passed through a series of selection steps designed to lead to predetermined results (eg higher tumor specific activity) without the need for prior knowledge. the resulting viral mechanism that is responsible for that outcome. The resulting collection of oncolytic virus can then be screened in a pre-clinical model to select oncolytic virus with the desired therapeutic characteristics.
The directed evolution is applied to human adenovirus, one of many viruses developed as oncolytic agents, to create highly selective and potent oncolytic vaccines. As a result of this process, ColoAd1 (new chimeric member of group B adenovirus) is generated. This hybrid of Adenp and Ad3 serotype adenoviruses demonstrates a much higher potency and tumor selectivity than control viruses (including Ad5, Ad11p and Ad3) and is confirmed to produce about two more log of viral progeny in newly isolated human colon tumor tissue than in tissue matching normal.
Attenuation
Attenuation involves the removal of viral genes, or gene regions, to eliminate the function of virus that can be disposed in tumor cells, but not in normal cells, thus making the virus safer and more tumor-specific. Cancer cells and virus-infected cells have similar changes in their cell signaling pathways, especially those that regulate progression through the cell cycle. Viral genes whose function of changing pathways can be disposed in cells where the path is damaged, but not in cells where the pathways are active.
The enzyme thymidine kinase and the ribonucleotide reductase in the cell are responsible for DNA synthesis and are only expressed in the cells that actively replicate. This enzyme is also present in certain viral genomes (eg HSV, vaccinia) and allows viral replication in a (non-replicate) rest cell, so if they are inactive by a mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.
Targeting tumor
There are two main approaches to yield tumor selectivity: transductional and non-transductional targeting.
- Transductional targeting involves modifying the virus layer protein to target tumor cells while reducing entry to non-tumor cells. This approach to tumor selectivity primarily focuses on adenovirus and HSV-1, although it is entirely feasible with other viruses.
- Non-transductional targeting involves changing the viral genome so that it can replicate only in cancer cells, most often as part of the attenuation of viruses.
- Transcriptional targeting can also be used, where important parts of the viral genome are placed under the control of tumor-specific promoters. The suitable promoter should be active in the tumor but is inactive in most normal tissues, especially the liver, which is the organ most exposed to viruses born from the blood. Many such promoters have been identified and studied for the treatment of various cancers.
- Similarly, viral replication can be well tuned with the use of artificial target sites of microRNAs (miRNA) or miRNA response elements (MREs). Different expressions of miRNA between healthy tissue and tumors make it possible to create an oncolytic virus that is designed from a particular tissue of interest while allowing its replication in tumor cells.
Double targeting with transductional and non-transductional targeting methods is more effective than just one form of targeting.
Gene reporter
Both in the laboratory and in the clinic it is useful to have a simple way to identify cells infected by experimental virus. This can be done by supplementing the virus with a 'reporter gene' that is usually absent in the viral genome, which encodes an easily identifiable protein marker. One example of such a protein is GFP (Green fluorescent protein) which, when present in an infected cell, will cause a fluorescent green glow emitted when stimulated by blue light. The advantage of this method is that this method can be used on living cells and in patients with superficially infected lesions, this allows confirmation of rapid, non-invasive viral infections. Another example of a useful visual marker in living cells is luciferase, an enzyme from fireflies in the presence of luciferin, emitting light that can be detected by special cameras.
The E. coli beta-glucuronidase and beta-galactosidase enzymes can also be encoded by some viruses. This enzyme, in the presence of a particular substrate, can produce intense colored compounds that are useful for visualizing infected cells and also for measuring gene expression.
Modify to increase oncolytic activity
Oncolytic virus can be used against cancer in additional ways to lysis the infected cells.
Genes suicide
Viruses can be used as vectors for the transmission of gene suicide, encoding enzymes that can metabolize non-toxic pro-drugs given separately into powerful cytotoxins, which can diffuse and kill adjacent cells. One herpes simplex virus, which encodes the suicidal gene kinase thymidine, has evolved into phase III clinical trials. The herpes simplex virus thymidine kinase phosphorylates pro-drugs, ganciclovir, which are then fed into DNA, blocking DNA synthesis. The selectivity of oncolytic viral tumors ensures that the genes of suicide are only expressed in cancer cells, but the 'observer effect' on surrounding tumor cells has been described by some suicidal gene systems.
Emphasis of angiogenesis
Angiogenesis (formation of blood vessels) is an important part of mass tumor mass formation. Angiogenesis can be inhibited by the expression of several genes, which can be transmitted to cancer cells in the viral vector, resulting in suppression of angiogenesis, and oxygen starvation in the tumor. Cell infection with gene-containing viruses for angiostatin and endostatin synthesis inhibits tumor growth in mice. Increased antitumor activity has been demonstrated in the recombinant vaccinia virus that encodes antibodies to anti-angiogenic therapy and with HSV1716 variants that express angiogenesis inhibitors.
Radioiodine
The addition of symbian sodium-iodide (NIS) genes to the viral genome causes infected tumor cells to express NIS and accumulate iodine. When combined with radioiodine therapy allows local radiotherapy of the tumor, as it is used to treat thyroid cancer. Radioiodine can also be used to visualize viral replication in the body using gamma cameras. This approach has been successfully used preclinically with adenovirus, measles virus and vaccinia virus.
Approved therapeutic agents
- Talimogene laherparepvec (OncoVEX GM-CSF), aka T-vec, by Amgen, successfully completed phase III trials for advanced melanoma in March 2013. In October 2015, the US FDA approved T-VEC, Imlygic , for the treatment of melanoma in patients with non-operable tumors. became the first oncolytic agent approved in the western world. It is based on herpes simplex virus (HSV-1). It has also been tested in Phase I trials for pancreatic cancer and Phase III trials on head and neck cancer along with Cisplatin chemotherapy and radiotherapy.
Clinical research
In the period 2014-2016 a number of clinical trials were initiated for a wide range of oncolytic viral products, reflecting the ongoing clinical development of this therapy class.
This is in conjunction with conventional cancer therapies that the oncolytic virus often shows the most promise, because combined therapy operates synergistically with no obvious negative effects.
Clinical test
Onyx-015 underwent a trial in conjunction with chemotherapy before being abandoned in the early 2000s. Combined treatment provides a greater response than treatment alone, but the results are not entirely conclusive. Vaccinia GL-ONC1 virus was studied in experiments combined with chemotherapy and radiotherapy as Standard Treatment for newly diagnosed patients with head & amp; cancer of the neck. Herpes simplex virus, adenovirus, reovirus and murine leukemia virus also undergo clinical trials as part of combination therapy.
Pre-clinical research
Chen et al. (2001) used CV706, prostate-specific adenovirus, in conjunction with radiotherapy in prostate cancer in mice. Combined treatment results in a synergistic increase in cell death, as well as a significant increase in the size of the viral explosion (the number of virus particles released from each cell lysis). No change in viral specificity was observed.
SEPREHVIR (HSV-1716) has also shown synergies in pre-clinical research when used in combination with some cancer chemotherapy.
Bevacizumab anti-angiogenic drugs (anti-VEGF antibodies) have been shown to reduce the inflammatory response to oncolytic HSV and increase virotherapy in mice. Modified oncolytic influenza virus vaccines coding single chain anti-VEGF antibodies (mimicking Bevacizumab) have been shown to have significantly increased antitumor activity than parental virus in animal models.
In fiction
In science fiction, the concept of oncolytic virus was first introduced to the public in Jack Williamson's novel Dragon's Island, published in 1951, although Williamson's imaginative virus is based on bacteriophages rather than the mammalian virus. Dragon Island is also known as the source of the term "genetic engineering".
The Hollywood film plot I Am Legend is based on the premise that epidemics around the world are caused by the healing of viruses for cancer.
See also
- Oncovirus, a virus that can cause cancer
- Measles viruses encode sympathizers of human thyroid sodium iodide (MV-NIS)
References
Further reading
Source of the article : Wikipedia
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