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| __NOTOC__
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| {{SI}}
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| {{CMG}}
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| ==Overview==
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| '''Talimogene laherparepvec''' (''tal im' oh jeen la her" pa rep' vek''), ('''T-Vec''', tradenamed '''Imlygic''', formerly called OncoVex<sup>GM-CSF</sup>)<ref>{{cite web|title=Talimogene laherparepvec|url=http://adisinsight.springer.com/drugs/800015278|publisher=AdisInsight|accessdate=16 October 2016}}</ref> is a [[biopharmaceutical]] drug to treat [[melanoma]] lesions that cannot be operated on; it is injected directly into the lesion.<ref name=Fukuhara2016rev/> As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis.<ref name=USlabel/>
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| Around half of people treated with T-Vec in clinical trials experienced fatigue and chills; around 40% had fever, around 35% had nausea, and around 30% had flu-like symptoms as well as pain at the injection site. The reactions were mild to moderate in severity; 2% of people had severe reactions and these were generally [[cellulitis]].<ref name=EMAlabel/>
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| T-Vec is a genetically engineered herpes virus (an [[oncolytic herpes virus]]). Two gene were removed – one that shuts down an individual cell's defenses, and another that helps the virus evade the immune system – were removed, 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.<ref name=Evans2016rev/><ref name=Fukuhara2016rev/>
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| The drug was created and initially developed by BioVex, Inc. and was continued by [[Amgen]], which acquired BioVex in 2011.<ref name=Acquistion>{{cite news|title=Amgen to Buy BioVex, Maker of Cancer Drugs|url=http://www.nytimes.com/2011/01/25/business/25amgen.html?_r=0|work=Bloomberg News via The New York Times|date=24 January 2011}}</ref> It was the first [[oncolytic virus]] approved in the West; it was approved in the US in October 2015 and provisionally approved in Europe in December 2015.<ref name=Reuters>{{cite web |url=http://www.reuters.com/article/2015/10/27/us-amgen-fda-idUSKCN0SL2YH20151027|title=FDA approves Amgen's Injected Immunotherapy for Melanoma|date=27 October 2015|publisher=Reuters}}</ref><ref name=Evans2016rev/>
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| ==Medical uses==
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| T-Vec is delivered locally by injecting it directly into melanoma lesions.<ref name=USlabel/>
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| In the US and Europe, T-Vec is used to treat melanoma lesions that cannot be operated on that are on or in the skin it is injected directly into the lesion; the population is more restricted in Europe.<ref name=USlabel>{{cite web|title=Imlygic label|url=http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM469575.pdf|publisher=FDA|accessdate=16 October 2016|date=October 2015}}</ref><ref name=EMAlabel>{{cite web|title=Imlygic|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002771/human_med_001941.jsp&mid=WC0b01ac058001d124|publisher=European Medicines Agency|accessdate=16 October 2016}} See [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002771/WC500201079.pdf Annex 1: Summary of Product Characteristics]; last updated September 7, 2016.</ref>
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| It has not been proven to extend survival nor to prevent metastases.<ref name=USlabel/><ref name=EMAlabel/>
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| The drug should not be used for people with very [[Immunodeficiency|weak immune system]].<ref name=EMAlabel/> Women should take precautions not to become pregnant while taking T-Vec and pregnant and nursing women should not take it.<ref name=EMAlabel/>
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| ==Adverse effects==
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| Around half of people treated with T-Vec in clinical trials experienced fatigue and chills; around 40% had fever, around 35% had nausea, and around 30% had flu-like symptoms as well as pain at the injection site. The reactions were mild to moderate in severity; 2% of people had severe reactions and these were generally [[cellulitis]].<ref name=EMAlabel/>
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| More than 10% of people had [[edema]], headache, cough, vomiting, diarrhea, constipation, muscle pain, or joint pain. Between 1% and 10% developed cold sores, pain or infection in the lesion, [[anemia]], immune mediated events (like vasculitis, pneumonia, worsening psoriasis, or glomerulonephritis), dehydration, confusion, anxiety, depression, dizziness, insomnia, ear pain, [[tachycardia|fast heart beating]], [[deep vein thrombosis]], high blood pressure, flushing, shortness of breath when exercising, sore throat, symptoms of the [[common cold]], stomach pain, back pain, groin pain, weight loss, or oozing from the injection site.<ref name=EMAlabel/>
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| Like wild [[herpes simplex virus]], T-Vec may persist in neurons exposed to it, and it may cause latent infections.<ref name=EMAlabel/>
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| ==Pharmacology==
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| T-Vec is taken up by normal cells and cancer cells like the wild type [[herpes simplex virus]], it is cleared in the same way.<ref name=EMAlabel/> Bioavailability and systemic concentrations have not been measured since the drug replicates once it is injected.<ref name=EMAlabel/>
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| ==Mechanism==
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| T-Vec directly destroys the cancer cells it infects; it was also designed to stimulate an immune response but as of 2016, there was no evidence of this.<ref name=Evans2016rev/><ref name=Fukuhara2016rev/>
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| The virus invades both cancerous and healthy cells, but it cannot replicate in healthy cells because it lacks [[Infected cell protein 34.5]] (ICP34.5). When cells are infected with a virus they shut down and die, but ICP34.5 blocks this [[cellular stress response|stress response]], allowing the virus to hijack the cell's [[Translation (biology)|translation]] machinery to replicate itself. A herpesvirus lacking the gene coding for ICP34.5 cannot replicate in normal cells. However, in many cancer cells the stress response is already disrupted, so a virus lacking ICP34.5 can still replicate in them. After the virus has replicated many times, the cell swells and finally bursts, killing the cell and releasing the copies of the virus, which can then infect nearby cells.<ref name=Fukuhara2016rev/><ref name=Agarwalla2012rev>{{cite journal|last1=Agarwalla|first1=PK|last2=Aghi|first2=MK|title=Oncolytic herpes simplex virus engineering and preparation.|journal=Methods in molecular biology (Clifton, N.J.)|date=2012|volume=797|pages=1–19|pmid=21948465|doi=10.1007/978-1-61779-340-0_1}}</ref>
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| While T-Vec is using the cells's translation machinery to replicate, it also uses it make the cell create [[GM-CSF]]. In theory, the GM-CSF that is secreted or released when the cancer cell bursts, attracts [[dendritic cells]] to the site, which pick up the tumor antigens, process them, and then present them on their surface to [[Cytotoxic T cell|cytotoxic (killer) T cells]] which in turn sets of an immune response. Whether GM-CSF produced from T-Vec is actually causing such an immune response in people to whom T-Vec was administered, was not certain as of 2016.<ref name=Evans2016rev/><ref name=Fukuhara2016rev/>
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| ==Composition==
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| T-Vec is a [[biopharmaceutical]] drug; it is an [[oncolytic herpes virus]] that was created by [[genetic engineering|genetically engineering]] a strain of [[herpes simplex virus 1]] (HSV-1) taken from a person infected with the virus, rather than a laboratory strain.<ref name=Evans2016rev/> Both copies of the viral gene coding for [[Infected cell protein 34.5|ICP34.5]] were deleted and replaced with the gene coding for human [[GM-CSF]], and the gene coding for [[Infected cell protein 47|ICP47]] was removed.<ref name=Evans2016rev/><ref name=Fukuhara2016rev>{{cite journal|last1=Fukuhara|first1=H|last2=Ino|first2=Y|last3=Todo|first3=T|title=Oncolytic virus therapy: A new era of cancer treatment at dawn.|journal=Cancer science|date=3 August 2016|pmid=27486853|url=http://onlinelibrary.wiley.com/doi/10.1111/cas.13027/full|doi=10.1111/cas.13027|pmc=5084676|volume=107|pages=1373-1379}}</ref><ref>{{cite journal|last1=Liu|first1=BL, et al|title=ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties.|journal=Gene therapy|date=February 2003|volume=10|issue=4|pages=292–303|pmid=12595888|doi=10.1038/sj.gt.3301885}}</ref> In wild herpes virus, ICP47 suppresses the immune response to the virus; it was removed because the drug was designed with the intention of activating the immune system.<ref name=Fukuhara2016rev/>
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| ==History==
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| The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named [[H101 virus|H101]] by Shanghai Sunway Biotech. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.<ref name="pmid16507823">{{cite journal |doi=10.1093/jnci/djj111 |title=China Approves World's First Oncolytic Virus Therapy for Cancer Treatment |year=2006 |last1=Garber |first1=K. |journal=JNCI Journal of the National Cancer Institute |volume=98 |issue=5 |pages=298–300 |pmid=16507823}}</ref>
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| T-Vec was created and initially developed by BioVex, Inc. under the brand OncoVEX<sup>GM-CSF</sup>; development was continued by [[Amgen]], which acquired BioVex in 2011.<ref name=Acquistion/><ref name=Evans2016rev/> BioVex had been founded in 2000, based on research by Robert Coffin at University College London,<ref>{{cite news|last1=Timmerman|first1=Luke|title=BioVex Raises $40M for Cancer-Fighting Virus |url=http://www.xconomy.com/boston/2009/03/30/biovex-raises-40m-for-cancer-fighting-virus/#|work=Xconomy|date=30 March 2009}}</ref> and moved its headquarters to Woburn, MA in 2005, leaving about half its employees in the UK.<ref>{{cite news|last1=Timmerman|first1=Luke|title=BioVex Viral Treatment Shrinks Melanoma Tumors in Trial|url=http://www.xconomy.com/boston/2008/06/01/biovex-viral-treatment-shrinks-melanoma-tumors-in-trial/|work=Xconomy|date=1 June 2008}}</ref>
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| The phase II clinical trial in melanoma was published in 2009<ref name=Senzer2009>Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor–encoding, second-generation oncolytic herpesvirus in patents with unresectable metastatic melanoma. ''J Clin Oncol''. 2009;27:5763–5771. Available [http://jco.ascopubs.org/content/27/34/5763.long here]</ref> and the Phase III trial was published in 2013.<ref name=And2013>Andtbacka RHI, Collichio FA, Amatruda T et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. ''J Clin Oncol'' 31, 2013 (suppl; abstr LBA9008). Available [http://meetinglibrary.asco.org/content/117592-132 here]</ref>
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| T-vec was approved by the US FDA to treat melanoma in October 2015 and this was the first approval of an oncolytic virus in the West; <ref name=Reuters/> it was provisionally approved by the EMA in December of that year – continued marketing approval depended on further clinical results.<ref name=EMAlabel/><ref name=Evans2016rev>{{cite journal|last1=Bilsland|first1=AE|last2=Spiliopoulou|first2=P|last3=Evans|first3=TR|title=Virotherapy: cancer gene therapy at last?|journal=F1000Research|date=2016 |volume=5|pmid=27635234 |url=https://f1000research.com/articles/5-2105/v1|doi=10.12688/f1000research.8211.1|pmc=5007754|pages=2105}}</ref>
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| ==Society and culture==
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| Amgen estimated that T-Vec would be priced at $65,000 per patient at the time it was first approved.<ref>{{cite news|title=FDA’s US approval of Imlygic is the first for a viral oncology therapy|url=http://www.thejournalofprecisionmedicine.com/fdas-us-approval-of-imlygic-is-the-first-for-a-viral-oncology-therapy/|work=The Journal of Precision Medicine|date=5 November 2015}}</ref>
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| ==Research==
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| As of 2016, T-vec had been studied in early stage clinical trials in [[pancreatic cancer]], [[soft-tissue sarcoma]], and [[head and neck squamous-cell carcinoma]]; it had also been tested in combination with [[checkpoint inhibitor]]s [[ipilimumab]] and [[pembrolizumab]].<ref name=Evans2016rev/>
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| ==See also==
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| *[[Virotherapy]]
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| *[[Oncolytic adenovirus]]
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| ==References==
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| {{Reflist|30em}}
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| [[Category:Virotherapy]]
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| [[Category:Immunomodulating drugs]]
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| [[Category:Amgen]]
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| [[Category:Experimental cancer treatments]]
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| [[Category:Simplexviruses]]
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| [[Category:Biotechnology]]
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