Parts of this article (those related to HSV1716 clinical trials) need to be updated. Please help update this article to reflect recent events or newly available information.(September 2015)
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). These attenuated versions are constructed by deleting viral genes required for infecting or replicating inside normal cells but not cancer cells, such as
ICP34.5, ICP6/UL39, and
ICP47.
HSV1716
HSV1716 is a first generation
oncolytic virus developed by the
Glasgow Institute of Virology, 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 variant 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
High grade
glioma: Three phase I trials have been completed and two phase II trials are in preparation.[6][7]
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
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.[1] A direct comparison of NV1020 and G207 in a
mouse model of
peritoneal cancer showed that NV1020 is more effective at lower doses.[18]
Clinical trials
A Phase I/II study completed in 2008 evaluating NV1020 for treatment of metastatic
colorectal cancer in the liver.[19] 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.[20][18]
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.[21]
It is a second-generation
herpes simplex virus based on the JS1 strain and expressing the immune stimulatory factor
GM-CSF.[22][23] Like other oncolytic versions of HSV it has a deletion of the gene encoding ICP34.5, which provides tumor selectivity.[24] It also has a deletion of the gene encoding ICP47, a protein that inhibits antigen presentation,[25] 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.
^Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, et al. (November 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.
PMID15334111.
S2CID14604628.
^Mace AT, Ganly I, Soutar DS, Brown SM (August 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.
PMID18615711.
S2CID43914133.
^Clinical trial number NCT01721018 for "Intrapleural Administration of HSV1716 to Treat Patients With Malignant Pleural Mesothelioma" at
ClinicalTrials.gov
^Clinical trial number NCT00931931 for "HSV1716 in Patients With Non-Central Nervous System (Non-CNS) Solid Tumors" at
ClinicalTrials.gov
^Clinical trial number NCT00028158 for "Safety and Effectiveness Study of G207, a Tumor-Killing Virus, in Patients With Recurrent Brain Cancer" at
ClinicalTrials.gov
^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
^Sze DY, Iagaru AH, Gambhir SS, De Haan HA, Reid TR (January 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.
PMID21895536.
^"OncoVEXGM-CSF RAC Submission"(PDF). NIH Genetic Modification Clinical Research Information System (GeMCRIS®). Archived from
the original(PDF) on 28 May 2010. Retrieved 1 April 2013.
^Hu JC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, et al. (November 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.
PMID17121894.
S2CID30005391.