Oncolytic herpes virus

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Oncolytic herpes virus
Herpes simplex virus TEM B82-0474 lores.jpg
TEM micrograph of a herpes simplex virus.
Virus classification
Group: Group I (dsDNA)
Order: Herpesvirales
Family: Herpesviridae
Subfamily: Alphaherpesvirinae
Genus: Simplexvirus
Species: Herpes simplex virus 1
Variety: Oncolytic herpes virus

Many variants of herpes simplex virus have been considered for viral therapy of cancer; the early development of these was thoroughly reviewed in the journal Cancer Gene Therapy in 2002.[1] This page describes (in the order of development) the most notable variants—those tested in clinical trials: G207, HSV1716, NV1020 and Talimogene laherparepvec (previously Oncovex-GMCSF).

Electron Micrograph of herpes virus


HSV1716 is a first generation oncolytic virus developed by The Institute of Virology, Glasgow, UK, and subsequently by Virttu Biologics (formerly Crusade Laboratories, a spin-out from The Institute of Virology), to selectively destroy cancer cells. The virus has the trade name SEPREHVIR. It is based on the herpes simplex virus (HSV-1). The HSV1716 strain has a deletion of the gene ICP34.5. ICP34.5 is a neurovirulence gene (enabling the virus to replicate in neurons of the brain and spinal cord). Deletion of this gene provides the property of tumor-selective replication to the virus (i.e. largely prevents replication in normal cells, while still allowing replication in tumor cells), although it also reduces replication in tumor cells as compared to wild type HSV.[2][3]

A vital part of the normal mechanism of HSV-1, the ICP34.5 protein has been proposed to condition post-mitotic cells for viral replication. With no ICP34.5 gene, the HSV-1716 variant is unable to overcome normal defences of healthy differentiated cells (mediated by PKR) to replicate efficiently. However, tumour cells have much weaker PKR-linked defences, which may be the reason why HSV1716 effectively kills a wide range of tumour cell lines in tissue culture.

An HSV1716 variant, HSV1716NTR is an oncolytic virus generated by inserting the enzyme NTR into the virus HSV1716 as a GDEPT strategy.[4] In-vivo, administration of the prodrug CB1954 to athymic mice bearing either A431 or A2780 tumour xenografts, 48 hours after intra-tumoral injection of HSV1790, resulted in a marked reduction in tumour volumes and significantly improved survival compared to administration of virus alone. A similar approach has been taken with a variants of HSV1716 that expresses the noradrenaline transporter to deliver radioactive iodine into individual infected cancer cells, by tagging a protein that cancer cells transport. The nor-adrenaline transporter specifically transports a compound containing radioactive iodine across the cell membrane, using genes from the virus. The only cells in the body that receive a significant radiation dose are those infected and their immediate neighbours.[5]

Clinical trials[edit]


G207 was constructed as a second-generation vector from HSV-1 laboratory strain F, with ICP34.5 deleted and the ICP6 gene inactivated by insertion of the E. coli LacZ gene.[12]

Two phase I clinical trials in glioma were completed.[13][14][15] The results of the first trial were published simultaneously with the first trial of HSV1716 in 2000, with commentators praising the demonstration of safety of these viruses when injected into brain tumours but also expressing disappointment that viral replication could not be demonstrated due to the difficulty of taking biopsies from brain tumours.[16]


NV1020 is an oncolytic herpes virus initially developed by Medigene Inc. and licensed for development by Catherex Inc. in 2010.[17] NV1020 has a deletion of just one copy of the ICP34.5 gene and ICP6 is intact.[18] A direct comparison of NV1020 and G207 in a mouse model of peritoneal cancer showed that NV1020 is more effective at lower doses.[19]

Clinical trials[edit]

A Phase I/II study completed in 2008 evaluating NV1020 for treatment of metastatic colorectal cancer in the liver.[20] The study assessed tumour response by CT scan and FDG-PET scans, showing 67% of patients had an initial increase in tumour size then followed by a decrease in 64% of patients.[21][19]

Talimogene laherparepvec[edit]

Talimogene laherparepvec is the USAN name for the oncolytic virus also known as 'OncoVEX GM-CSF'. It was developed by BioVex Inc. (Woburn, MA, USA & Oxford, UK) until BioVex was purchased by Amgen in January 2011.[22]

It is a second-generation herpes simplex virus based on the JS1 strain and expressing the immune stimulatory factor GM-CSF.[23][24] Like other oncolytic versions of HSV it has a deletion of the gene encoding ICP34.5, which provides tumor selectivity.[25] It also has a deletion of the gene encoding ICP47, a protein that inhibits antigen presentation,[26] and an insertion of a gene encoding GM-CSF, an immune stimulatory cytokine.[2][3] Deletion of the gene encoding ICP47 also puts the US11 gene (a late gene) under control of the immediate early ICP47 promoter. The earlier and greater expression of US11 (also involved in overcoming PKR-mediated responses) largely overcomes the reduction in replication in tumor cells of ICP34.5-deleted HSV as compared to wild type virus, but without reducing tumor selectivity.

Clinical trials[edit]

  • Phase III in stage IIIB, IIIC or IV melanoma. Amgen released positive data on this trial in March 2013 demonstrating it to have met its primary endpoint (durable response rate) with a high degree of statistical significance, the first positive phase 3 trial of an oncolytic virus in the western world.[27][28][29]
  • Expanded access trial in melanoma.[30]
  • Phase III trial in head and neck cancer, in combination with radiotherapy and cisplatin chemotherapy. This was halted by Amgen on the acquisition of BioVex.[31]

See also[edit]


  1. ^ Varghese, Susan; Rabkin, Samuel D (2002). "Oncolytic herpes simplex virus vectors for cancer virotherapy". Cancer Gene Therapy 9 (12): 967–78. doi:10.1038/sj.cgt.7700537. PMID 12522436. 
  2. ^ a b Mohr, I; Gluzman, Y (1996). "A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function". The EMBO Journal 15 (17): 4759–66. PMC 452208. PMID 8887567. 
  3. ^ a b Liu, B L; Robinson, M; Han, Z-Q; Branston, R H; English, C; Reay, P; McGrath, Y; Thomas, S K et al. (2003). "ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties". Gene Therapy 10 (4): 292–303. doi:10.1038/sj.gt.3301885. PMID 12595888. 
  4. ^ Braidwood, Lynne; Dunn, Paul D; Hardy, Susan; Evans, T R Jeffry; Brown, S Moira (2009). "Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy". Anticancer Research 29 (6): 2159–66. PMID 19528476. 
  5. ^ Sorensen, A.; Mairs, R. J.; Braidwood, L.; Joyce, C.; Conner, J.; Pimlott, S.; Brown, M.; Boyd, M. (2012). "In Vivo Evaluation of a Cancer Therapy Strategy Combining HSV1716-Mediated Oncolysis with Gene Transfer and Targeted Radiotherapy". Journal of Nuclear Medicine 53 (4): 647–54. doi:10.2967/jnumed.111.090886. PMID 22414636. 
  6. ^ Harrow, S; Papanastassiou, V; Harland, J; Mabbs, R; Petty, R; Fraser, M; Hadley, D; Patterson, J et al. (2004). "HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: Safety data and long-term survival". Gene Therapy 11 (22): 1648–58. doi:10.1038/sj.gt.3302289. PMID 15334111. 
  7. ^ Papanastassiou, V; Rampling, R; Fraser, M; Petty, R; Hadley, D; Nicoll, J; Harland, J; Mabbs, R; Brown, M (2002). "The potential for efficacy of the modified (ICP 34.5−) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: A proof of principle study". Gene Therapy 9 (6): 398–406. doi:10.1038/sj.gt.3301664. PMID 11960316. 
  8. ^ Mace, Alastair T. M.; Ganly, Ian; Soutar, David S.; Brown, S. Moira (2008). "Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma". Head & Neck 30 (8): 1045–51. doi:10.1002/hed.20840. PMID 18615711. 
  9. ^ MacKie, Rona M; Stewart, Barry; Brown, S Moira (2001). "Intralesional injection of herpes simplex virus 1716 in metastatic melanoma". The Lancet 357 (9255): 525–6. doi:10.1016/S0140-6736(00)04048-4. PMID 11229673. 
  10. ^ Clinical trial number NCT01721018 for "Intrapleural Administration of HSV1716 to Treat Patients With Malignant Pleural Mesothelioma" at ClinicalTrials.gov
  11. ^ Clinical trial number NCT00931931 for "HSV1716 in Patients With Non-Central Nervous System (Non-CNS) Solid Tumors" at ClinicalTrials.gov
  12. ^ Mineta, Toshihiro; Rabkin, Samuel D.; Yazaki, Takahito; Hunter, William D.; Martuza, Robert L. (1995). "Attenuated multi–mutated herpes simplex virus–1 for the treatment of malignant gliomas". Nature Medicine 1 (9): 938–43. doi:10.1038/nm0995-938. PMID 7585221. 
  13. ^ Markert, J M; Medlock, M D; Rabkin, S D; Gillespie, G Y; Todo, T; Hunter, W D; Palmer, C A; Feigenbaum, F et al. (2000). "Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: Results of a phase I trial". Gene Therapy 7 (10): 867–74. doi:10.1038/sj.gt.3301205. PMID 10845725. 
  14. ^ Clinical trial number NCT00028158 for "Safety and Effectiveness Study of G207, a Tumor-Killing Virus, in Patients With Recurrent Brain Cancer" at ClinicalTrials.gov
  15. ^ Clinical trial number NCT00157703 for "G207 Followed by Radiation Therapy in Malignant Glioma" at ClinicalTrials.gov
  16. ^ Kirn, D H (2000). "A tale of two trials: Selectively replicating herpesviruses for brain tumors". Gene Therapy 7 (10): 815–6. doi:10.1038/sj.gt.3301213. PMID 10845717. 
  17. ^ "MediGene AG divests Oncolytic Herpes Simplex Viruses (oHSV) program to Catherex, Inc" (Press release). MediGene AG. April 13, 2010. Retrieved May 7, 2013. 
  18. ^ Varghese, S; Rabkin, SD (2002). "Oncolytic herpes simplex virus vectors for cancer virotherapy". Cancer gene therapy 9 (12): 967–78. doi:10.1038/sj.cgt.7700537. PMID 12522436. 
  19. ^ a b Geevarghese, Sunil K.; Geller, David A.; De Haan, Hans A.; Hörer, Markus; Knoll, Anette E.; Mescheder, Axel; Nemunaitis, John; Reid, Tony R. et al. (2010). "Phase I/II Study of Oncolytic Herpes Simplex Virus NV1020 in Patients with Extensively Pretreated Refractory Colorectal Cancer Metastatic to the Liver". Human Gene Therapy 21 (9): 1119–28. doi:10.1089/hum.2010.020. PMC 3733135. PMID 20486770. 
  20. ^ Clinical trial number NCT00149396 for "Safety and Efficacy of a Genetically Engineered Herpes Simplex Virus NV1020 to Treat Colorectal Cancer Metastatic to Liver" at ClinicalTrials.gov
  21. ^ Sze, Daniel Y.; Iagaru, Andrei H.; Gambhir, Sanjiv S.; De Haan, Hans A.; Reid, Tony R. (2012). "Response to Intra-Arterial Oncolytic Virotherapy with the Herpes Virus NV1020 Evaluated by [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography". Human Gene Therapy 23 (1): 91–7. doi:10.1089/hum.2011.141. PMID 21895536. 
  22. ^ "Amgen, Form 8-K, Current Report, Filing Date Jan 26, 2012" (PDF). secdatabase.com. Retrieved Jan 8, 2013. 
  23. ^ "OncoVEXGM-CSF RAC Submission" (PDF). NIH Genetic Modification Clinical Research Information System (GeMCRIS®). Retrieved 1 April 2013. 
  24. ^ Hu, Jennifer C.C.; Coffin, Robert S.; Davis, Ceri J.; Graham, Nicola J.; Groves, Natasha; Guest, Peter J.; Harrington, Kevin J.; James, Nicholas D. et al. (2006). "A Phase I Study of OncoVEXGM-CSF, a Second-Generation Oncolytic Herpes Simplex Virus Expressing Granulocyte Macrophage Colony-Stimulating Factor". Clinical Cancer Research 12 (22): 6737–47. doi:10.1158/1078-0432.CCR-06-0759. PMID 17121894. 
  25. ^ Raafat, Nermin; Sadowski-Cron, Charlotte; Mengus, Chantal; Heberer, Michael; Spagnoli, Giulio C.; Zajac, Paul (2012). "Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope". International Journal of Cancer 131 (5): E659–69. doi:10.1002/ijc.27362. PMID 22116674. 
  26. ^ Broughton, Sophie E.; Dhagat, Urmi; Hercus, Timothy R.; Nero, Tracy L.; Grimbaldeston, Michele A.; Bonder, Claudine S.; Lopez, Angel F.; Parker, Michael W. (2012). "The GM-CSF/IL-3/IL-5 cytokine receptor family: From ligand recognition to initiation of signaling". Immunological Reviews 250 (1): 277–302. doi:10.1111/j.1600-065X.2012.01164.x. PMID 23046136. 
  27. ^ Clinical trial number NCT00769704 for "Efficacy and Safety Study of OncoVEXGM-CSF Compared to GM-CSF in Melanoma" at ClinicalTrials.gov
  28. ^ Kaufman, Howard L; Bines, Steven D (2010). "OPTIM trial: A Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma". Future Oncology 6 (6): 941–9. doi:10.2217/fon.10.66. PMID 20528232. 
  29. ^ "Amgen Announces Top-Line Results Of Phase 3 Talimogene Laherparepvec Trial In Melanoma" (Press release). Amgen. Mar 19, 2013. Retrieved May 7, 2013. 
  30. ^ Clinical trial number NCT01368276 for "An Extended Use Study of Safety and Efficacy of OncoVEXGM-CSF in Melanoma" at ClinicalTrials.gov
  31. ^ Clinical trial number NCT01161498 for "Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer" at ClinicalTrials.gov
  32. ^ Clinical trial number NCT00402025 for "OncoVEX GM-CSF in Patients With Unresectable Pancreatic Cancer" at ClinicalTrials.gov

External links[edit]