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 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; 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. In the 1940s-50s some of the earliest human clinical trials with oncolytic viruses were started. 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
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 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
The oncolytic virus Rigvir developed at the Institute of Microbiology in Latvia is the first virotherapy to pass all stages of clinical development and was registered in 2004 in Latvia (national registration). Since 2004 Rigvir is approved and since 2008 Rigvir is available in pharmacies of Latvia. Virotherapy with Rigvir is successfully used in Latvia and by patients from more than 25 countries around the world. Recent retrospective study published in Melanoma Research revealed that IB-IIC melanoma patients treated with oncolytic virus RIGVIR were 4.39–6.57-fold lower mortality than those, who according to melanoma treatment guidelines did not receive virotherapy and were only observed. Also in 2015 Rigvir was included into the Latvian National guidelines for treatment of skin cancer and melanoma. 
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 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.
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. 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. Promising research results warrant its clinical development in human patients.
The experimental virotherapy that has progressed the furthest in clinical trials (as of 2013) is Talimogene laherparepvec. 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
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.
Trovax is an immunotherapy that uses a pox-virus bearing the tumour antigen 5T4, to induce an immune response against a variety of cancer types. The therapy was developed by Oxford BioMedica and failed to improve overall survival in a phase 3 trial in renal cell carcinoma. New phase II trials have since begun at Cardiff University (UK) with colorectal cancer and at the Velindre Cancer Centre (Cardiff, UK) with malignant pleural mesothelioma.
- Ring; Blair, Edward D. (2000). Genetically engineered viruses : development and applications. Oxford: Bios. ISBN 1859961037.
- Kelly, E; Russell, SJ (April 2007). "History of oncolytic viruses: genesis to genetic engineering". Molecular therapy : the journal of the American Society of Gene Therapy 15 (4): 651–9. doi:10.1038/sj.mt.6300108. PMID 17299401.
- 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.
- "Clinical virotherapy: four historically significant clinical trials".
- 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.
- Latvian State Agency of Medicines Registry | http://www.zva.gov.lv/zalu-registrs/?iss=1&lang=en&q=Rigvir&ON=&SN=&NAC=on&RN=&ESC=on&AK=&SAT=on&RA=&DEC=on&LB=&PIM=on | accessed 21 January 2015
- Doniņa, Simona; Strēle, Ieva; Proboka, Guna; Auziņš, Jurģis; Alberts, Pēteris; Jonsson, Björn; Venskus, Dite; Muceniece, Aina (2015). "Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study". Melanoma Research 25 (5): 421–426. doi:10.1097/CMR.0000000000000180.
- Cancer Virotherapy Journal | https://www.cancervirotherapy.eu/cancer-virotherapy-pdf-version.php | accessed 23 November 2015
- Witlox AM, Van Beusechem VW, Molenaar B, Bras H, Schaap GR, Alemany R, Curiel DT, Pinedo HM, Wuisman PI, Gerritsen WR., Conditionally replicative adenovirus with tropism expanded towards integrins inhibits osteosarcoma tumor growth in vitro and in vivo. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):61-7
- Clinical Trial for Delta-24-RGD for Recurrent Malignant Gliomas
- Isracast news article on virotherapy March 2006
- "Welcome to Genelux - intro". Genelux.com. Retrieved 2012-02-03.
- 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.
- 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.
- "Safety Study of GL-ONC1, an Oncolytic Virus, in Patients With Advanced Solid Tumors". ClinicalTrials.gov. Retrieved 2012-02-03.
- Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer
- "Why GenVec’s TNFerade adenovector did not work in the Phase III pancreatic cancer trial?". 14 April 2010.
- Amato, RJ; Hawkins, RE; Kaufman, HL; Thompson, JA; Tomczak, P; Szczylik, C; McDonald, M; Eastty, S; Shingler, WH; de Belin, J; Goonewardena, M; Naylor, S; Harrop, R (Nov 15, 2010). "Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study". Clinical cancer research : an official journal of the American Association for Cancer Research 16 (22): 5539–47. doi:10.1158/1078-0432.CCR-10-2082. PMID 20881001. Retrieved 5 May 2013.
- Keen, E. C. (2013). "Beyond phage therapy: Virotherapy of protozoal diseases". Future Microbiology 8 (7): 821–823. doi:10.2217/FMB.13.48.
- 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.