Virotherapy

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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. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

Oncolytic virotherapy[edit]

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;[1] 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.[2] In the 1940s–1950s some of the earliest human clinical trials with oncolytic viruses were started.[3][4] However, for several years research in this field was delayed due to the inadequate technology available. Research has now started to proceed more quickly in finding ways to use viruses therapeutically.

As well as the direct anti-cancer effect, oncolytic viruses are also capable of inducing an anti-tumour immune response.

Viral gene therapy[edit]

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.

Viral immunotherapy[edit]

Viral immunotherapy uses viruses to introduce specific antigens to the patient's immune system. 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/bactera or even human disease antigens, for example cancer antigens.

Specific projects and products[edit]

Oncolytic viruses[edit]

RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004.[5] It is wild type ECHO-7, a member of echovirus family.[6] The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s.[6] The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan.[6][7] As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment.[8][9]

In 2004, researchers from University of Texas genetically programmed a type of common cold virus Adenovirus Delta-24-RGD to attack glioblastoma multiforme. Later other researchers[10] have tried tests on mice where 9 out of 10 mice have shown degeneration of tumours and prolonged survival. A drug grade virus was approved for clinical trials on humans in 2009.[11]

In 2006 researchers from the Hebrew University succeeded in isolating a variant of the Newcastle disease virus (NDV-HUJ), which usually affects birds, in order to specifically target cancer cells.[12] The researchers tested the new virotherapy on patients with glioblastoma multiforme and achieved promising results for the first time.

Vaccinia virus, a virus credited for the eradication of smallpox, is being developed as an oncolytic virus, e.g. GL-ONC1 and JX-594.[13] Promising research results[14][15] warrant its clinical development in human patients.[16]

The experimental virotherapy that has progressed the furthest in clinical trials (as of 2013) is Talimogene laherparepvec.[17] It is based on an engineered version of herpes simplex virus which has also been engineered to express GM-CSF. This virus is being developed by Amgen who reported that a pivotal phase 3 study in melanoma had met its primary endpoint (durable response rate) with a very high degree of significance in March 2013, the first positive phase 3 study with an oncolytic virus in the western world.

Viral gene therapy[edit]

ProSavin is one of a number of therapies in the Lentivector platform under development by Oxford BioMedica. It delivers to the brain the genes for three enzymes important in the production of dopamine, a deficiency of which causes Parkinson's disease.

TNFerade (a non replicating TNF gene therapy virus) failed a phase III trial for pancreatic cancer.[18]

Protozoal virotherapy[edit]

Recent papers have proposed the use of viruses to treat infections caused by protozoa.[19][20]

History[edit]

Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.[21]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ "Clinical virotherapy: four historically significant clinical trials". 
  4. ^ 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. 
  5. ^ "Latvijas Zāļu reģistrs". www.zva.gov.lv. Retrieved 2017-12-17. 
  6. ^ 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 5308590Freely accessible. PMID 28224120. 
  7. ^ "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. 
  8. ^ Gorski D (18 September 2017). "Rigvir: Another unproven and dubious cancer therapy to be avoided". Science-Based Medicine. 
  9. ^ 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. 
  10. ^ Witlox AM, Van Beusechem VW, Molenaar B, Bras H, Schaap GR, Alemany R, Curiel DT, Pinedo HM, Wuisman PI, Gerritsen WR (2004). "Conditionally replicative adenovirus with tropism expanded towards integrins inhibits osteosarcoma tumor growth in vitro and in vivo". Clin. Cancer Res. 10 (Pt 1): 61–67. doi:10.1158/1078-0432.ccr-0609-03. PMID 14734452. 
  11. ^ Clinical Trial for Delta-24-RGD for Recurrent Malignant Gliomas
  12. ^ "Viruses: The new cancer hunters". IsraCast (News article). March 1, 2006. Retrieved July 22, 2016. 
  13. ^ "Welcome to Genelux - intro". Genelux.com. Retrieved 2012-02-03. 
  14. ^ Zhang, Q; Yu, YA; Wang, E; Chen, N; Danner, RL; Munson, PJ; Marincola, FM; Szalay, AA (2007). "Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus". Cancer Research. 67 (20): 10038–46. doi:10.1158/0008-5472.CAN-07-0146. PMID 17942938. 
  15. ^ Kelly, KJ; Woo, Y; Brader, P; Yu, Z; Riedl, C; Lin, SF; Chen, N; Yu, YA; Rusch, VW; Szalay, Aladar A.; Fong, Yuman (2008). "Novel oncolytic agent GLV-1h68 is effective against malignant pleural mesothelioma". Human gene therapy. 19 (8): 774–82. doi:10.1089/hum.2008.036. PMC 2940611Freely accessible. PMID 18754710. 
  16. ^ "Safety Study of GL-ONC1, an Oncolytic Virus, in Patients With Advanced Solid Tumors". ClinicalTrials.gov. Retrieved 2012-02-03. 
  17. ^ Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer
  18. ^ "Why GenVec's TNFerade adenovector did not work in the Phase III pancreatic cancer trial?". 14 April 2010. 
  19. ^ 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. 
  20. ^ 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. 
  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. 

Further reading[edit]

  • Ring, Christopher J. A.; Blair, Edward D. (2000). Genetically engineered viruses: development and applications. Oxford: Bios. ISBN 1859961037. OCLC 45828140.