Talimogene laherparepvec

Talimogene laherparepvec, brand name Imlygic, is used to treat melanoma that cannot be operated on.

Talimogene laherparepvec is a genetically engineered herpes virus.

It is  an oncolytic herpes virus.

It is injected directly into a subset of lesions which generates a systemic immune response against the recipient’s cancer.

A four year analysis from the pivotal phase 3 study upon which TVEC was approved showed a 31.5% response rate with a 16.9% complete response 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.

Use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5%.

Pregnancy category-contraindicated

Routes of administration- Injection

Side effects: half of patients 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. 

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), 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.

2% of people had severe reactions: generally cellulitis.

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.

T-VEC stimulates an immune response against the patient’s cancer.

Its use may be associated with regression of tumors which have not been injected with talimogene laherparepvec.

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

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;

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.

It is taken up by normal cells and cancer cells like the wild type herpes simplex virus, it is cleared in the same way.

It directly destroys the cancer cells it infects, inducing a systemic immune response against the patient’s cancer.

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). 

Cells are infected with a virus shut down and die.

ICP34.5 blocks cells 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. 

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.

While talimogene laherparepvec is using the cell’s translation machinery to replicate, it also uses it to make the cell create GM-CSF. 

When the cancer cell bursts, GM-CSF is released.

GM-CSF attracts  dendritic cells to the site, which recognize antigens, process them, and present them on their surface to cytotoxic (killer) T cells which manifests a immune response.

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: both copies of the viral gene coding for ICP34.5 are deleted and replaced with the gene coding for human GM-CSF, and the gene coding for ICP47 was removed.

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.

Talimogene laherparepvec is the first approved oncolytic immunotherapy, designed to provide systemic anti-tumor effects through the induction of an anti-tumor immune response.

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