 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 names | T-Vec |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a616006 |
| License data | |
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| Routes of administration | Injection |
| ATC code | |
| Legal status | |
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| Identifiers | |
| CAS Number | |
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| KEGG | |
Talimogene laherparepvec, sold under the brand nameImlygic among others, is abiopharmaceutical medication used to treatmelanoma 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]
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 generallycellulitis.[8]
Talimogene laherparepvec is a genetically engineered herpes virus (anoncolytic 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 humanGM-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 byAmgen, which acquired BioVex in 2011.[10] It was one of the firstoncolytic immunotherapy approved globally; it was approved in the US in October 2015 and approved in Europe in December 2015.[11][9][12]
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]
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 generallycellulitis.[8]
More than 10% of people hadedema, 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 andvitiligo[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 thecommon cold, stomach pain, back pain, groin pain, weight loss, or oozing from the injection site.[8]
Talimogene laherparepvec is taken up by normal cells and cancer cells like the wild typeherpes simplex virus, it is cleared in the same way.[8]
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 lacksInfected cell protein 34.5 (ICP34.5). When cells are infected with a virus they shut down and die, but ICP34.5 blocks thisstress response, allowing the virus to hijack the cell'stranslation 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 createGM-CSF. GM-CSF is secreted or released when the cancer cell bursts, attractingdendritic cells to the site, which pick up the tumor antigens, process them, and then present them on their surface tocytotoxic (killer) T cells which in turn sets off an immune response.[9][5]
Talimogene laherparepvec is abiopharmaceutical drug; it is anoncolytic herpes virus that was created bygenetically engineering a strain ofherpes 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 forICP34.5 were deleted and replaced with the gene coding for humanGM-CSF, and the gene coding forICP47 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]
The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus namedH101 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.[18]
Talimogene laherparepvec was created and initially developed by BioVex, Inc. under the brand OncoVEXGM-CSF. Development was continued byAmgen, which acquired BioVex in 2011.[10][9] BioVex was founded in 1999, based on research by Robert Coffin atUniversity College London,[19] and moved its headquarters toWoburn, Massachusetts in 2005, leaving about half its employees in the UK.[20]
Thephase II clinical trial in melanoma was published in 2009[21] and thephase III trial was published in 2013.[22]
Talimogene laherparepvec was approved by the USFood and Drug Administration to treatmelanoma in October 2015. It was the first approval of anoncolytic virus and the first approval of a gene therapy in the West.[11] It was approved by theEuropean Medicines Agency in December of that year.[8][9]
Amgen estimated that talimogene laherparepvec would be priced atUS$65,000 per patient at the time it was approved.[23]
As of 2016, talimogene laherparepvec has been studied in early stage clinical trials inpancreatic cancer,soft-tissue sarcoma, andhead and neck squamous-cell carcinoma; it had also been tested in combination withcheckpoint inhibitorsipilimumab andpembrolizumab.[9]
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