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
Gene therapy
Target geneGM-CSF
VectorHerpes simplex virus 1
Names
Pronunciation/təˈlɪmən ləˌhɜːrpəˈrɛpvɛk/ tə-LIM-ə-jeen lə-HUR-pə-REP-vek
Trade namesT-Vec, Imlygic, OncoVexGM-CSF, others
Clinical data
Drug classOncolytic virus[1]
Main usesMelanoma[2]
Side effectsTiredness, fever, nausea, pain at the site of injection, herpes infection[2]
Pregnancy
category
  • Contraindicated[3]
Routes of
use
Injection
Typical doseUp to 4 ml[2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa616006
Legal
License data
Legal status
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)

Talimogene laherparepvec (T-Vec), sold under the brand name Imlygic, is a medication used to treat melanoma that cannot be operated on.[2] Specifically it is used for melanoma within and just under the skin.[4] It is given by directly injecting into lesions.[2] It has not been shown to affected life expectancy.[4]

Common side effects include tiredness, fever, nausea, and pain at the site of injection.[2] Other side effects include may include herpes infections, cellulitis or skin death at the site of injection, vasculitis, and plamacytoma.[2] Use during pregnancy may harm the baby.[2] It should not be used in people with a severely impaired immune system.[1] It is a genetically engineered herpes virus (an oncolytic virus) which infects and multiplies inside melanoma cells, resulting in their death.[1] It also stimulates an immune response against the cancer.[1]

Talimogene laherparepvec was approved in the United States and Europe in 2015.[1][4] In the United States it may cost up to 23,000 per dose as of 2021.[5] In the United Kingdom this amount costs the NHS about £6,700.[6]

Medical uses

In the US, talimogene laherparepvec is approved to treat Stage IIIb-IVM1c melanoma 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.[7][8]

Talimogene laherparepvec extends survival in people with Stage IIIb-IVM1a melanoma and those who have not received prior systemic therapy for melanoma.[9]

Dosage

Talimogene laherparepvec is delivered by injecting it directly into tumors, thereby creating a systemic anti-tumor immune response.[7]

The first injection is given using a lower strength solution followed by further injections using a higher strength solution.[1] Injections are done every two weeks for at least six months.[1]

The amount used depends on the size of the lesion up to a maximum of 4 ml.[2]

Side effects

Around half of people experience 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.[8]

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[10] ), 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.[8]

Pharmacology

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.[8]

Mechanism

Talimogene laherparepvec directly destroys the cancer cells it infects, inducing a systemic immune response against the patient's cancer.[11][12]

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.[12][13]

While talimogene laherparepvec is using the cell's translation machinery to replicate, it also uses it to 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.[11][12]

Chemistry

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.[11] 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.[11][12][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.[12]

History

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.[16][11] BioVex was founded in 1999, based on research by Robert Coffin at University College London,[17] and moved its headquarters to Woburn, Massachusetts in 2005, leaving about half its employees in the UK.[18]

The phase II clinical trial in melanoma was published in 2009[19] and the phase III trial was published in 2013.[20]

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.[21] It was approved by the European Medicines Agency in December of that year.[8][11]

Society and culture

Economics

Amgen estimated that talimogene laherparepvec would be priced at US$65,000 per patient at the time it was approved.[22]

Research

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.[11]

See also

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Imlygic". Retrieved 21 September 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Talimogene Laherparepvec Monograph for Professionals". Drugs.com. Retrieved 21 September 2021.
  3. "Talimogene laherparepvec (Imlygic) Use During Pregnancy". Drugs.com. 25 December 2019. Retrieved 2 April 2020.
  4. 4.0 4.1 4.2 "Imlygic (talimogene laherparepvec)". U.S. Food and Drug Administration (FDA).
  5. "Imlygic Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 22 September 2021.
  6. BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2021 – March 2021. p. 1007. ISBN 978-0-85711-369-6.
  7. 7.0 7.1 "Imlygic label" (PDF). FDA. October 2015. Retrieved 16 October 2016. For label updates see FDA index page for BLA 125518
  8. 8.0 8.1 8.2 8.3 8.4 "Imlygic". European Medicines Agency. Retrieved 16 October 2016. See Annex 1: Summary of Product Characteristics; last updated September 7, 2016.
  9. Conry RM, Westbrook B, McKee S, Norwood TG (3 April 2018). "Talimogene laherparepvec: First in class oncolytic virotherapy". Hum Vaccin Immunother. 14 (4): 839–846. doi:10.1080/21645515.2017.1412896. PMC 5893211. PMID 29420123.
  10. Harrington KJ, Michielin O, Malvehy J, Pezzani Grüter I, Grove L, Frauchiger AL, 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. PMC 5546812. PMID 28814886. 101514322.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 11.6 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.
  12. 12.0 12.1 12.2 12.3 12.4 Fukuhara H, Ino Y, Todo T (October 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.
  13. Agarwalla PK, Aghi MK (2012). "Oncolytic herpes simplex virus engineering and preparation". Oncolytic Viruses. 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, Robinson M, Han ZQ, Branston RH, English C, Reay P, 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 (March 2006). "China approves world's first oncolytic virus therapy for cancer treatment". Journal of the National Cancer Institute. 98 (5): 298–300. doi:10.1093/jnci/djj111. PMID 16507823.
  16. "Amgen to Buy BioVex, Maker of Cancer Drugs". Bloomberg News via The New York Times. 24 January 2011.
  17. Timmerman L (30 March 2009). "BioVex Raises $40M for Cancer-Fighting Virus". Xconomy.
  18. Timmerman L (1 June 2008). "BioVex Viral Treatment Shrinks Melanoma Tumors in Trial". Xconomy.
  19. Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, et al. (December 2009). "Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma". Journal of Clinical Oncology. 27 (34): 5763–71. doi:10.1200/JCO.2009.24.3675. PMID 19884534.
  20. Andtbacka RH, Collichio FA, Amatruda T, Senzer NN, Chesney J, Delman KA, 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". Journal of Clinical Oncology. 31 (supplement): LBA9008.
  21. "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
  22. "FDA's US approval of Imlygic is the first for a viral oncology therapy". The Journal of Precision Medicine. 5 November 2015.

External links

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