Oncolytic Virotherapy

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches utilize three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout utilizes RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths.[1] In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

Infection and Cancer shrinkage

Oncolytic virotherapy is not a new idea – as early as the mid 1950s doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement;[2] this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.

In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumours.[3] In the 1940s–1950s some of the earliest human clinical trials with oncolytic viruses were started.[4][5]

In 2015 the FDA approved the marketing of talimogene laherparepvec, a genetically engineered herpes virus, to treat melanoma lesions that cannot be operated on; it is injected directly into the lesion.[6] As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis.[7]

Two genes were removed from the virus – one that shuts down an individual cell’s defenses, and another that helps the virus evade the immune system – and a gene for human GM-CSFwas added. The drug works by replicating in cancer cells, causing them to burst; it was also designed to stimulate an immune response but as of 2016, there was no evidence of this.[8][6] The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011.[9] It was the first oncolytic virus approved in the West.[8]

Viral gene therapy most frequently uses non-replicating viruses to deliver therapeutic genes to cells with genetic malfunctions. Early efforts while technically successful, faced considerable delays due to safety issues as the uncontrolled delivery of a gene into a host genome has the potential to disrupt tumour suppressing genes and induce cancer, and did so in two cases. Immune responses to viral therapies also pose a barrier to successful treatment, for this reason eye therapy for genetic blindness is attractive as the eye is an immune privileged site, preventing an immune response.

An alternative form of viral gene therapy is to deliver a gene which may be helpful in preventing disease that would not normally be expressed in the natural disease condition. For example, the growth of new blood vessels in cancer, known as angiogenesis, enables tumours to grow larger. However, a virus introducing anti-angiogenic factors to the tumour may be able to slow or halt growth.

Unlike traditional vaccines, in which attenuated or killed virus/bacteria is used to generate an immune response, viral immunotherapy uses genetically engineered viruses to present a specific antigen to the immune system. That antigen could be from any species of virus/bacteria or even human disease antigens, for example cancer antigens.

Vaccines are another method of virotherapy that use attenuated or inactivated viruses to develop immunity to disease. An attenuated virus is a weakened virus that incites a natural immune response in the host that is often undetectable. The host also develops potentially life-long immunity due to the attenuated virus’s similarity to the actual virus. Inactivated viruses are killed viruses that present a form of the antigen to the host. However, long-term immune response is limited.[10]

There are two general approaches to develop these viruses using applied evolutionary techniques: Jennerian and Pastorian. The Jennerian method involves selecting similar viruses from non-human organisms to protect against a human virus while Pastorian methods use serial passage. This Pastorian method is very similar to directive evolution of oncolytic viruses. Selected viruses that target humans are passed through multiple non-human organisms for multiple generations. Over time the viruses adapt to the foreign environments of their new hosts. These now maladapted viruses have minimal capacity for harming humans and are used as attenuated viruses for clinical use.[11] An important consideration is to not reduce the replicative ability of the virus beyond the point where the immune system response will be compromised. A secondary immune response would therefore be insufficient to provide protection against the live virus should it be reintroduced to the host.

Rigvir ? TNFerade

RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004.[12] It is wild type ECHO-7, a member of echovirusfamily.[13] The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s.[13] The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan.[13][14] As of 2017 there was no strong evidence that RIGVIR is an effective cancer treatment.[15][16] 

There are multiple anecdotal evidenced-based cases where patients have improved and even went into remission with Rigvir. But additional trials would be warranted (See file on Rigvir) TNFerade (a non replicating TNF gene therapy virus) failed a phase III trial for pancreatic cancer.[17]

Viruses have been explored as a means to treat infections caused by protozoa.[18][19] One such protozoa that potential virotherapy treatments have explored is Naegleria fowleri which causes primary amebic meningoencephalitis (PAM). With a mortality rate of 95%, this disease-causing eukaryote has one of the highest pathogenic fatalities known. Chemotherapeutic agents that target this amoeba for treating PAM have difficulty crossing blood-brain barriers. However, the driven evolution of virulent viruses of protozoal pathogens (VVPPs) may be able to develop viral therapies that can more easily access this eukaryotic disease by crossing the blood-brain barrier in a process analogous to bacteriophages. These VVPPs would also be self-replicating and therefore require infrequent administration with lower doses, thus potentially reducing toxicity. [20] While these treatment methods for protozoal disease may show great promise in a manner similar to bacteriophage viral therapy, a notable hazard is the evolutionary consequence of using viruses capable of eukaryotic pathogenicity. VVPPs will have evolved mechanisms of DNA insertion and replication that manipulate eukaryotic surface proteins and DNA editing proteins. VVPP engineering must therefore control for viruses that may be able to mutate and thereby bind to surface proteins and manipulate the DNA of the infected host. Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.[21]

 

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Prostate Cancer Top

 

References

  1. ^ Stephen, Sam. “How Science Is Using Viruses To Make You Better – CPI”. CPI. Retrieved 31 October 2018.
  2. ^ Kelly, E; Russell, SJ (April 2007). “History of oncolytic viruses: genesis to genetic engineering”. Molecular Therapy. 15 (4): 651–9. doi:10.1038/sj.mt.6300108. PMID 17299401.
  3. ^ Moore, AE (May 1949). “The destructive effect of the virus of Russian Far East encephalitis on the transplantable mouse sarcoma 180″. Cancer. 2 (3): 525–34. doi:10.1002/1097-0142(194905)2:3<525::AID-CNCR2820020317>3.0.CO;2-O. PMID 18131412.
  4. ^ “Clinical virotherapy: four historically significant clinical trials”.
  5. ^ Huebner, RJ; Rowe, WP; Schatten, WE; Smith, RR; Thomas, LB (Nov–Dec 1956). “Studies on the use of viruses in the treatment of carcinoma of the cervix”. Cancer. 9 (6): 1211–8. doi:10.1002/1097-0142(195611/12)9:6<1211::AID-CNCR2820090624>3.0.CO;2-7. PMID 13383455.
  6. ^ Jump up to: a b Fukuhara, H; Ino, Y; Todo, T (3 August 2016). “Oncolytic virus therapy: A new era of cancer treatment at dawn”. Cancer Science. 107: 1373–1379. PMC 5084676. PMID 27486853.
  7. ^ “Imlygic label” (PDF). FDA. October 2015. Retrieved 16 October 2016. For label updates see FDA index page for BLA 125518
  8. ^ Jump up to: a b Bilsland, AE; Spiliopoulou, P; Evans, TR (2016). “Virotherapy: cancer gene therapy at last?”. F1000Research. 5: 2105. doi:10.12688/f1000research.8211.1. PMC 5007754. PMID 27635234.
  9. ^ “Amgen to Buy BioVex, Maker of Cancer Drugs”. Bloomberg News via The New York Times. 24 January 2011.
  10. ^ Services, U.S. Department of Health and Human. “Vaccines.gov”. www.vaccines.gov.
  11. ^ Hanley, KA (December 2011). “The double-edged sword: How evolution can make or break a live-attenuated virus vaccine”. Evolution. 4 (4): 635–643. doi:10.1007/s12052-011-0365-y. PMID 22468165.
  12. ^ “Latvijas Zāļu reģistrs”. www.zva.gov.lv. Retrieved 2017-12-17.
  13. ^ Jump up to: a b c Babiker, HM; Riaz, IB; Husnain, M; Borad, MJ (2017). “Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma”. Oncolytic virotherapy. 6: 11–18. doi:10.2147/OV.S100072. PMC 5308590. PMID 28224120.
  14. ^ “Feasibility study for registration of medicine RIGVIR with the European Medicine Agency”. European Commission. 2016-01-08. Archived from the original on 2016-11-02. Retrieved 2016-11-02. However, further use and commercialisation in the EU is prevented as EU regulations require cancer medicines to be registered centrally through the European Medicine Agency (EMA). National registrations are not considered.
  15. ^ Gorski D (18 September 2017). “Rigvir: Another unproven and dubious cancer therapy to be avoided”. Science-Based Medicine.
  16. ^ Gorski, David (25 September 2017). “Ty Bollinger’s “The Truth About Cancer” and the unethical marketing of the unproven cancer virotherapy Rigvir”. Science-Based Medicine.
  17. ^ “Why GenVec’s TNFerade adenovector did not work in the Phase III pancreatic cancer trial?”. 14 April 2010.
  18. ^ Keen, E. C. (2013). “Beyond phage therapy: Virotherapy of protozoal diseases”. Future Microbiology. 8 (7): 821–823. doi:10.2217/FMB.13.48. PMID 23841627.
  19. ^ Hyman, P.; Atterbury, R.; Barrow, P. (2013). “Fleas and smaller fleas: Virotherapy for parasite infections”. Trends in Microbiology. 21 (5): 215–220. doi:10.1016/j.tim.2013.02.006. PMID 23540830.
  20. ^ Keen, Eric C (July 2013). “Beyond phage therapy: virotherapy of protozoal diseases”. Future Microbiology. 8 (7): 821–823. doi:10.2217/fmb.13.48.
  21. ^ Sepkowitz, Kent (24 August 2009). “West Nile Made Its U.S. Debut in the 1950s, in a Doctor’s Syringe”. The New York Times. p. D5.
  • Ring, Christopher J. A.; Blair, Edward D. (2000). Genetically engineered viruses: development and applications. Oxford: Bios. ISBN 1859961037. OCLC 45828140

 

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