Talimogene laherparepvec

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Talimogene laherparepvec
Herpes simplex virus TEM B82-0474 lores.jpg
Transmission electron micrograph of an unmodified herpes simplex virus
Clinical data
Trade namesT-Vec, Imlygic, Oncovex
AHFS/Drugs.comMonograph
MedlinePlusa616006
License data
Pregnancy
category
  • US: N (Not classified yet) [1]
  • Contraindicated
Routes of
administration
Injection
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG

Talimogene laherparepvec[a] is a biopharmaceutical drug to treat melanoma that cannot be operated on; it is injected directly into a subset of lesions which generates a systemic immune response against the patient's cancer.[3] The final four year analysis from the pivotal phase 3 study upon which TVEC was approved by the FDA showed a 31.5% response rate with a 16.9% CR rate. There was also a substantial and statistically significant survival benefit in patients with earlier metastatic disease (stages IIIb-IVM1a) and in patients who hadn't received prior systemic treatment for melanoma. The earlier stage group had a reduction in the risk of death of approximately 50% with one in four patients appearing to have met, or be close to be reaching, the medical definition of cure.[4] Real world use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5% Int J Cancer.[5]

Around half of people treated with talimogene laherparepvec 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.[6]

Talimogene laherparepvec is a genetically engineered herpes virus (an oncolytic herpes virus). Two genes were removed – 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 against the patient's cancer, which has been demonstrated by multiple pieces of data, including regression of tumors which have not been injected with talimogene laherparepvec.[7][3]

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 immunotherapy approved globally; it was approved in the US in October 2015 and approved in Europe in December 2015.[9][7][10]

Medical uses[edit]

Talimogene laherparepvec is delivered by injecting it directly into tumors, thereby creating a systemic anti-tumor immune response.[11]

In the US, talimogene laherparepvec is FDA approved to treat Stage IIIb-IVM1c melanoma patients for whom surgical intervention is not appropriate and with tumors which can be directly injected; the EMA approved population in Europe is for Stage IIIb-IVM1a.[11][6]

Talimogene laherparepvec has been proven to significantly extend survival in patients with Stage IIIb-IVM1a melanoma and patients who have not received prior systemic therapy for melanoma.[medical citation needed]

Adverse effects[edit]

Around half of people treated with talimogene laherparepvec 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.[6]

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, glomerulonephritis and vitiligo[12] ), dehydration, confusion, anxiety, depression, dizziness, insomnia, ear pain, 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.[6]

Pharmacology[edit]

Talimogene laherparepvec is taken up by normal cells and cancer cells like the wild type herpes simplex virus, it is cleared in the same way.[6]

Mechanism[edit]

Talimogene laherparepvec directly destroys the cancer cells it infects, inducing a systemic immune response against the patient's cancer.[7][3]

The virus invades both cancerous and healthy cells, but it cannot productively replicate in healthy tissue 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 stress response, allowing the virus to hijack the cell's translation machinery to replicate itself. A herpesvirus lacking the gene coding for ICP34.5 cannot replicate in normal tissue. However, in many cancer cells the stress response is already disrupted, so a virus lacking ICP34.5 can still replicate in tumors. 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.[3][13]

While Talimogene laherparepvec is using the cells's translation machinery to replicate, it also uses it make the cell create GM-CSF. GM-CSF is secreted or released when the cancer cell bursts, attracting dendritic cells to the site, which pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells which in turn sets off an immune response. [7][3]

Composition[edit]

Talimogene laherparepvec is a biopharmaceutical drug; it is an oncolytic herpes virus that was created by genetically engineering a strain of herpes simplex virus 1 (HSV-1) taken from a person infected with the virus, rather than a laboratory strain.[7] Both copies of the viral gene coding for ICP34.5 were deleted and replaced with the gene coding for human GM-CSF, and the gene coding for ICP47 was removed.[7][3][14] 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.[3]

History[edit]

The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named 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.[15] Talimogene laherparepvec is the world's first approved oncolytic immunotherapy, i.e. it was also designed to provide systemic anti-tumor effects through the induction of an anti-tumor immune response.

Talimogene laherparepvec was created and initially developed by BioVex, Inc. under the brand OncoVEXGM-CSF. Development was continued by Amgen, which acquired BioVex in 2011.[8][7] BioVex was founded in 1999, based on research by Robert Coffin at University College London,[16] and moved its headquarters to Woburn, Massachusetts in 2005, leaving about half its employees in the UK.[17]

The phase II clinical trial in melanoma was published in 2009[18] and the phase III trial was published in 2013.[19]

Talimogene laherparepvec was approved by the U.S. Food and Drug Administration to treat melanoma in October 2015. It was the first approval of an oncolytic virus and the first approval of a gene therapy in the West.[9] It was approved by the European Medicines Agency in December of that year.[6][7]

Sales[edit]

Amgen estimated that talimogene laherparepvec would be priced at $65,000 per patient at the time it was approved.[20]

Research[edit]

As of 2016, talimogene laherparepvec 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 inhibitors ipilimumab and pembrolizumab.[7]

See also[edit]

Notes[edit]

  1. ^ /təˈlɪmən ləˌhɜːrpəˈrɛpvɛk/ tə-LIM-ə-jeen lə-HUR-pə-REP-vek (T-Vec, tradenamed Imlygic, formerly called OncoVexGM-CSF)[2]

References[edit]

  1. ^ "Talimogene laherparepvec (Imlygic) Use During Pregnancy". Drugs.com. 25 December 2019. Retrieved 2 April 2020.
  2. ^ "Talimogene laherparepvec". AdisInsight. Retrieved 16 October 2016.
  3. ^ a b c d e f g Fukuhara, H; Ino, Y; Todo, T (3 August 2016). "Oncolytic virus therapy: A new era of cancer treatment at dawn". Cancer Science. 107 (10): 1373–1379. doi:10.1111/cas.13027. PMC 5084676. PMID 27486853.
  4. ^ Andtbacka et al., Journal for ImmunoTherapy of Cancer (2019) 7:145
  5. ^ Franke et al., Int J Cancer. 2019 Aug 15;145(4):974–978. doi: 10.1002/ijc.32172. Epub 2019 Feb 21
  6. ^ a b c d e f "Imlygic". European Medicines Agency. Retrieved 16 October 2016. See Annex 1: Summary of Product Characteristics; last updated September 7, 2016.
  7. ^ a b c d e f g h i 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. ^ a b "Amgen to Buy BioVex, Maker of Cancer Drugs". Bloomberg News via The New York Times. 24 January 2011.
  9. ^ a b "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
  10. ^ "Imlygic (talimogene laherparepvec)". U.S. Food and Drug Administration (FDA). 1 March 2018. Archived from the original on 23 April 2019. Retrieved 1 April 2020.CS1 maint: unfit url (link)
  11. ^ a b "Imlygic label" (PDF). FDA. October 2015. Retrieved 16 October 2016. For label updates see FDA index page for BLA 125518
  12. ^ Harrington, K.J.; Michielin, O.; Malvehy, J.; Pezzani Grüter, I.; Grove, L; Dummer, R (August 2017). "A practical guide to the handling and administration of talimogene laherparepvec in Europe". OncoTargets and Therapy. 10: 3867–3880. doi:10.2147/OTT.S133699. ISSN 1178-6930. PMC 5546812. PMID 28814886. 101514322.
  13. ^ Agarwalla, PK; Aghi, MK (2012). Oncolytic herpes simplex virus engineering and preparation. Methods in Molecular Biology. 797. pp. 1–19. doi:10.1007/978-1-61779-340-0_1. ISBN 978-1-61779-339-4. PMID 21948465.
  14. ^ Liu, BL; et al. (February 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.
  15. ^ Garber, K. (2006). "China Approves World's First Oncolytic Virus Therapy for Cancer Treatment". JNCI Journal of the National Cancer Institute. 98 (5): 298–300. doi:10.1093/jnci/djj111. PMID 16507823.
  16. ^ Timmerman, Luke (30 March 2009). "BioVex Raises $40M for Cancer-Fighting Virus". Xconomy.
  17. ^ Timmerman, Luke (1 June 2008). "BioVex Viral Treatment Shrinks Melanoma Tumors in Trial". Xconomy.
  18. ^ 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 here
  19. ^ 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 here
  20. ^ "FDA's US approval of Imlygic is the first for a viral oncology therapy". The Journal of Precision Medicine. 5 November 2015.

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