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. 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

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]

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.[5] As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis.[6] 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-CSF was 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.[7][5] The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011.[8] It was the first oncolytic virus approved in the West.[7]

Viral gene therapy

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

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

Oncolytic viruses

RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004.[9] It is wild type ECHO-7, a member of echovirus family.[10] The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s.[10] The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan.[10][11] As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment.[12][13]

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[14] 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.[15]

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.[16] 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.[17] Promising research results[18][19] warrant its clinical development in human patients.[20]

Viral gene therapy

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.[21]

Protozoal virotherapy

Recent papers have proposed the use of viruses to treat infections caused by protozoa.[22][23]

History

Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.[24]

See also

References

  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. 1 2 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.
  6. ↑ "Imlygic label" (PDF). FDA. October 2015. Retrieved 16 October 2016. For label updates see FDA index page for BLA 125518
  7. 1 2 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.
  8. ↑ "Amgen to Buy BioVex, Maker of Cancer Drugs". Bloomberg News via The New York Times. 24 January 2011.
  9. ↑ "Latvijas Zāļu reģistrs". www.zva.gov.lv. Retrieved 2017-12-17.
  10. 1 2 3 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.
  11. ↑ "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.
  12. ↑ Gorski D (18 September 2017). "Rigvir: Another unproven and dubious cancer therapy to be avoided". Science-Based Medicine.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Clinical Trial for Delta-24-RGD for Recurrent Malignant Gliomas
  16. ↑ "Viruses: The new cancer hunters". IsraCast (News article). March 1, 2006. Retrieved July 22, 2016.
  17. ↑ "Welcome to Genelux - intro". Genelux.com. Retrieved 2012-02-03.
  18. ↑ 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.
  19. ↑ 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 2940611. PMID 18754710.
  20. ↑ "Safety Study of GL-ONC1, an Oncolytic Virus, in Patients With Advanced Solid Tumors". ClinicalTrials.gov. Retrieved 2012-02-03.
  21. ↑ "Why GenVec's TNFerade adenovector did not work in the Phase III pancreatic cancer trial?". 14 April 2010.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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

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