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 gene GM-CSF
Vector Herpes simplex virus 1
Clinical data
Trade names Imlygic, Oncovex
Other namesT-Vec
AHFS/Drugs.com Monograph
MedlinePlus a616006
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Pregnancy
category
  • Contraindicated
Routes of
administration 		Injection
ATC code
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Legal status
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KEGG

Talimogene laherparepvec, sold under the brand name Imlygic among others, is a biopharmaceutical medication used 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 recipient's cancer. [5] 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% complete response (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. [6] Real world use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5%. [7]

Contents

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. [8]

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. [9] [5]

The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011. [10] It was one of the first oncolytic immunotherapy approved globally; it was approved in the US in October 2015 and approved in Europe in December 2015. [11] [9] [12]

Medical uses

Talimogene laherparepvec is delivered by injecting it directly into tumors, thereby creating a systemic anti-tumor immune response. [2]

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. [2] [8]

Talimogene laherparepvec has been shown to extend survival in patients with Stage IIIb-IVM1a melanoma and patients who have not received prior systemic therapy for melanoma. [13]

Adverse effects

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. [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 [14] ), 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. [9] [5]

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. [5] [15]

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. [9] [5]

Composition

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. [9] 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. [9] [5] [16] 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. [5]

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. [17] 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.[ citation needed ]

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. [10] [9] BioVex was founded in 1999, based on research by Robert Coffin at University College London, [18] and moved its headquarters to Woburn, Massachusetts in 2005, leaving about half its employees in the UK. [19]

The phase II clinical trial in melanoma was published in 2009 [20] and the phase III trial was published in 2013. [21]

Talimogene laherparepvec was approved by the US 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. [11] It was approved by the European Medicines Agency in December of that year. [8] [9]

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 has 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. [9]

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses. Oncolytic viruses also have the ability to affect the tumor micro-environment in multiple ways.

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor</span> Mammalian protein found in Homo sapiens

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

<span class="mw-page-title-main">Viral vector</span> Biotechnology to deliver genetic material into a cell

Viral vectors are modified viruses designed to deliver genetic material into cells. This process can be performed inside an organism or in cell culture. Viral vectors have widespread applications in basic research, agriculture, and medicine.

Oncolytics Biotech Inc. is a Canadian company headquartered in Calgary, Alberta, that is developing an intravenously delivered immuno-oncolytic virus called pelareorep for the treatment of solid tumors and hematological malignancies. Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus that: induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses.

Pelareorep is a proprietary isolate of the unmodified human reovirus being developed as a systemically administered immuno-oncological viral agent for the treatment of solid tumors and hematological malignancies. Pelareorep is an oncolytic virus, which means that it preferentially lyses cancer cells. Pelareorep also promotes an inflamed tumor phenotype through innate and adaptive immune responses. Preliminary clinical trials indicate that it may have anti-cancer effects across a variety of cancer types when administered alone and in combination with other cancer therapies.

JX-594 is an oncolytic virus is designed to target and destroy cancer cells. It is also known as Pexa-Vec, INN pexastimogene devacirepvec) and was constructed in Dr. Edmund Lattime's lab at Thomas Jefferson University, tested in clinical trials on melanoma patients, and licensed and further developed by SillaJen.

Racotumomab is a therapeutic cancer vaccine for the treatment of solid tumors that is currently under clinical development by ReComBio, an international public-private consortium with the participation of the Center of Molecular Immunology at Havana, Cuba (CIM) and researchers from Buenos Aires University and National University of Quilmes in Argentina. It induces the patient's immune system to generate a response against a cancer-specific molecular target with the purpose of blocking tumor growth, slowing disease progression and ultimately increasing patient survival.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Abscopal effect</span> Hypothesis in the treatment of metastatic cancer

The abscopal effect is a hypothesis in the treatment of metastatic cancer whereby shrinkage of untreated tumors occurs concurrently with shrinkage of tumors within the scope of the localized treatment. R.H. Mole proposed the term "abscopal" in 1953 to refer to effects of ionizing radiation "at a distance from the irradiated volume but within the same organism".

<span class="mw-page-title-main">Jennerex</span>

Jennerex Biotherapeutics, Inc. was an American private biopharmaceutical company that developed the oncolytic viruses JX-594 and JX-929 among others. By creating oncolytic viruses that can (1) kill tumor cells directly through lysis, (2) activate the immune system by delivering genes that encode immunostimulants and by overcoming tumor cell-induced immunological tolerance, and (3) reduce tumor nutrient supply through the destruction of blood vessels, Jennerex aimed to create a novel approach to treating and possibly curing cancer.

<span class="mw-page-title-main">Oncolytic herpes virus</span>

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. This page describes the most notable variants—those tested in clinical trials: G207, HSV1716, NV1020 and Talimogene laherparepvec. 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.

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.

Infected cell protein 34.5 is a protein expressed by the γ34.5 gene in viruses such as herpes simplex virus; it blocks a cellular stress response to viral infection. It shares the C-terminal regulatory domain with protein phosphatase 1 subunit 15A/B.

A therapeutic vaccine is a vaccine which is administered after a disease or infection has already occurred. A therapeutic vaccine works by activating the immune system of a patient to fight an infection. A therapeutic vaccine differs from a prophylactic vaccine in that prophylactic vaccines are administered to individuals as a precautionary measure to avoid the infection or disease while therapeutic vaccines are administered after the individual is already affected by the disease or infection. A therapeutic vaccine fights an existing infection in the body rather than immunizing the body for protection against future diseases and infections. Therapeutic vaccines are mostly used against viral infections. Patients affected with chronic viral infections are administered with therapeutic vaccines, as their immune system is not able to produce enough efficient antibodies.

Transgene S.A. is a French biotechnology company founded in 1979. It is based in Illkirch-Graffenstaden, near Strasbourg, and develops and manufactures immunotherapies for the treatment of cancer.

Cytokines are polypeptides or glycoproteins that help immune cells communicate to each other to induce proliferation, activation, differentiation, and inflammatory or anti-inflammatory signals in various cell types. Studies utilizing cytokines for antitumor therapies has increased significantly since 2000, and different cytokines provide unique antitumor activities. Cytokines hinder tumor cell development mostly through antiproliferative or proapoptotic pathways but can also interrupt development indirectly by eliciting immune cells to have cytotoxic effects against tumor cells. Even though there are FDA-approved cytokine therapies, there are two main challenges associated with cytokine delivery. The first is that cytokines have a short half-life, so frequent administration of high doses is required for therapeutic effect. The second is that systemic toxicity could occur if the cytokines delivered cause an intense immune response, known as a cytokine storm.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. 1 2 3 "Imlygic- talimogene laherparepvec injection, suspension". DailyMed. 18 January 2022. Retrieved 16 March 2022.
  3. ↑ "Imlygic (talimogene laherparepvec)". U.S. Food and Drug Administration. 6 July 2022. Retrieved 19 November 2022.
  4. ↑ "Imlygic EPAR". European Medicines Agency (EMA). 16 December 2015. Retrieved 26 August 2024.
  5. 1 2 3 4 5 6 7 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.
  6. ↑ Andtbacka RH, Collichio F, Harrington KJ, Middleton MR, Downey G, Öhrling K, et al. (June 2019). "Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma". Journal for Immunotherapy of Cancer. 7 (1): 145. doi: 10.1186/s40425-019-0623-z . PMC   6554874 . PMID   31171039.
  7. ↑ Franke V, Berger DM, Klop WM, van der Hiel B, van de Wiel BA, Ter Meulen S, et al. (August 2019). "High response rates for T-VEC in early metastatic melanoma (stage IIIB/C-IVM1a)". International Journal of Cancer. 145 (4): 974–978. doi: 10.1002/ijc.32172 . PMID   30694555. S2CID   59340728.
  8. 1 2 3 4 5 6 "Imlygic". European Medicines Agency. Retrieved 16 October 2016. See Annex 1: Summary of Product Characteristics; last updated 7 September 2016.
  9. 1 2 3 4 5 6 7 8 9 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.
  10. 1 2 "Amgen to Buy BioVex, Maker of Cancer Drugs". Bloomberg News via The New York Times. 24 January 2011.
  11. 1 2 "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
  12. ↑ "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.{{cite web}}: CS1 maint: unfit URL (link)
  13. ↑ 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.
  14. ↑ Harrington KJ, Michielin O, Malvehy J, Pezzani Grüter I, Grove L, Frauchiger AL, et al. (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.
  15. ↑ Agarwalla PK, Aghi MK (2012). "Oncolytic Herpes Simplex Virus Engineering and Preparation". Oncolytic Viruses. Methods in Molecular Biology. Vol. 797. pp. 1–19. doi:10.1007/978-1-61779-340-0_1. ISBN   978-1-61779-339-4. PMID   21948465.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Timmerman L (30 March 2009). "BioVex Raises $40M for Cancer-Fighting Virus". Xconomy.{{cite news}}: CS1 maint: overridden setting (link)
  19. ↑ Timmerman L (1 June 2008). "BioVex Viral Treatment Shrinks Melanoma Tumors in Trial". Xconomy.{{cite news}}: CS1 maint: overridden setting (link)
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ "FDA's US approval of Imlygic is the first for a viral oncology therapy". The Journal of Precision Medicine. 5 November 2015. Archived from the original on 7 August 2020. Retrieved 16 October 2016.
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