Talimogen laherparepvec

Talimogen laherparepvec (T-Vec) belongs to the group of oncolytic immunotherapeutics (oncolytic virotherapy). This immunotherapeutic is a genetically modified herpes simplex virus, type 1 (HSV-1). Talimogene laherparepvec (T-VEC) demonstrated significant improvement in durable response rate, objective response rate and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. Talimogene laherparepvec is the first oncolytic viral therapy approved by the U.S. FDA for the treatment of advanced melanoma. The compound is also approved in Germany.

Talimogene laherparepvec (T-VEC) is attenuated by deletion of the viral herpes neurovirulence geneand its immunogenicity is enhanced by concomitant deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte-macrophage colony-stimulating factor(GM-CSF) gene, which promotes priming of T-cell responses. The viral agent is designed to detect melanoma cells, replicate within them and produce the immunostimulatory GM-CSF. Targeted infection of tumor cells with consecutive mass replication of the virus in the cell, leads to its destruction. It bursts. The induced viral oncolysis results in a systemically relevant anti-tumoural immune response, which sustainably and specifically attacks other tumour cell nests located in the body.

Deletion of ICP47 and ICP34.5 is proving to be very helpful in melanoma treatment. In some tumor cells, protein kinase R (PKR) is only slightly expressed or not expressed at all. PKR is a cellular kinase that normally shuts down protein synthesis in virus-infected cells. In the absence of ICP34.5, T-Vec can replicate in these cells but not in cells expressing PKR. As a result, T-Vec leads to tumor lysis, leaving normal cells unaffected. On the one hand, removal of ICP47 ensures that the immune system can recognize the infected tumor cells. On the other hand, viral replication is increased in the malignant cells. With the added encoded sequence hGM-CSF, the immune response to the tumor should be enhanced. Presumably, the virus with hGM-CSF promotes a systemic antitumor immune response and an effector T-cell response.

Talimogene laherparepvec showed significant improvement in durable response rate, objective response rate and progression-free survival in a randomised phase III clinical trial for patients with advanced melanoma.

Results for approval of Imlygic was evaluated in the open-label, multinational, randomized, Phase III OPTiM clinical trial. In this study, treatment success was measured in 436 patients with advanced, unresectable melanoma. Imlygic was compared to subcutaneous injection of GM-CSF. To give delayed immune-mediated antitumor effects a chance, treatment continued for at least six months (or until no injectable melanomas were detectable). Therapy was continued even if lesions initially grew or new ones were added.

The primary endpoint was defined as the durable response rate. This consisted of a partial or complete response for at least six months. Secondary endpoints assessed were overall survival (OS), overall response rate (ORR), time to response, duration of response, and time to treatment failure.

With Imlygic, 16.3 percent of subjects had a durable response to treatment, compared with only 2.1 percent with GM-CSF. The ORR was also in favor of Imlygic, with a ratio of 26.4 versus 5.7 percent. The drug also performed convincingly in terms of median OS, at 23.3 versus 18.9 months. The time to patient response to Imlygic was 4.1 months (vs. 3.7 months), and to treatment failure was 8.2 months (2.9 months).

An investigation of a subgroup concluded that oncolytic immunotherapy worked significantly better when lungs or other internal organs were not yet affected.

Talimogene laherparepvec and is indicated for the treatment of adults with unresectable, locally or distantly metastatic melanoma (stage IIIB, IIIC and IVM1a) without bone, brain, lung or visceral involvement.

No data are available on this. If a pregnant woman has a wild-type HSV-1 infection (primary or reactivated), there is a possibility of the virus crossing the placental barrier and a risk of transmission during delivery through viral shedding. HSV-1 wild-type infections have been associated with serious adverse effects including multi-organ failure and death when a fetus or newborn develops a herpes wild-type infection.

Imlygic is available as 106 and 108 plaque-forming units per ml (PFU/ml) solution for injection. The drug is injected intralesionally, i.e. directly into the melanoma, which must be visible, palpable or detectable by sonography. Starting from the injection site, the injection is administered in a fan-shaped manner into the tumour. This is to ensure an even distribution of the viruses. The amount to be applied depends on the shape and size of the melanoma. However, no more than 4 ml total injection volume may be injected.

For the first treatment the lower concentrated solution is available. After three weeks and every two weeks thereafter or when treatment is resumed, the higher concentration injection solution should be chosen. The manufacturer usually recommends a therapy duration of at least six months.

Fatigue (50.3%), chills (48.6%), pyrexia (42.8%), nausea (35.6%), flu-like illness (30.5%) and injection site pain (27.7%).

Herpes infections: herpes infections in patients treated with Imlygic occur more frequently: labial herpes; keratitis herpetica. Talimogene laherparepvec is sensitive to aciclovir. The risks and benefits of Imlygic treatment should be considered before using aciclovir or other antiviral agents indicated for the treatment of herpes infections. These agents may interfere with the efficacy of treatment when used systemically or topically directly at the injection site.

Cellulitis at the injection site: Necrosis or ulceration of tumour tissue may occur following treatment with Imlygic. The occurrence of cellulitis and systemic bacterial infections has been reported.

Immune-mediated events: glomerulonephritis, vasculitis, pneumonitis, worsening of psoriasis, and the occurrence of vitiligo have been reported.

Plasmocytoma at the injection site: Plasmocytoma around the injection site has been reported after use of Imlygic.

Obstructive respiratory disease may be exacerbated.

HSV-1 seronegative patients: Pyrexia, chills, and influenza-like illness, particularly within the period of the first 6 treatments, have been reported to occur at a greater incidence in patients who were initially HSV-1 seronegative than in those who were initially HSV-1 seropositive

Aciclovir or other antiviral agents may interfere with the effectiveness of treatment when used systemically or topically directly at the injection site.

Imlygic®

1. Bommareddy PK et al (2017) Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma. Am J Clin Dermatol 8:1-15.
2. Technical information: Imlygic