Talimogene laherparepvec

Talimogene laherparepvec is an oncolytic immunotherapy that is derived from HSV-1. Talimogene laherparepvec has been modified to replicate within tumours and to produce the immune stimulatory protein human GM-CSF. Talimogene laherparepvec causes the death of tumour cells and the release of tumour-derived antigens. It is thought that together with GM-CSF, it will promote a systemic anti-tumour immune response and an effector T-cell response. Mice that had complete regression of their primary tumours following treatment were resistant to subsequent tumour rechallenge.

The modifications to talimogene laherparepvec from HSV-1 include deletion of ICP34.5 and ICP47. Whereas anti-viral immune responses defend normal cells following infection by talimogene laherparepvec, tumours have been shown to be susceptible to injury and cell death from ICP34.5-deficient HSV-1 viruses, including talimogene laherparepvec. Deletion of ICP47 prevents down-regulation of antigen presentation molecules and increases the expression of HSV US11 gene, thereby enhancing viral replication in tumour cells.

Talimogene laherparepvec is a genetically modified and replication-competent HSV-1 virus. Therefore, its pharmacokinetics and biodistribution are driven by the site of intralesional injection, tumour-selective replication, and release from tumour tissue.

Absorption

Cellular uptake of talimogene laherparepvec occurs through HSV-1 receptors on tumours and non-tumour cells following local injection into tumours. As talimogene laherparepvec is injected and replicates intratumourally, bioavailability and systemic concentration of talimogene laherparepvec are not predictive of drug substance activity and therefore have not been evaluated.

Metabolism/elimination

Talimogene laherparepvec is cleared through general host-defence mechanisms (e.g. autophagy, adaptive immune responses). Talimogene laherparepvec is degraded by typical endogenous protein and DNA catabolic pathways. As with other wild-type HSV-1 infections, a latent pool of talimogene laherparepvec DNA may persist in neuronal cell bodies innervating the injection sites; therefore, the occurrence of latent infection with talimogene laherparepvec cannot be excluded.

Biodistribution (within the body) and viral shedding (excretion/secretion)

Talimogene laherparepvec DNA was quantified with a highly sensitive and specific quantitative Polymerase Chain Reaction (qPCR) assay which may not correlate with viral infectivity risk. Talimogene laherparepvec was also quantified in selected patient samples in clinical studies using viral infectivity assays at the injection sites and in some cases of potential herpetic lesions.

Clinical biodistribution, elimination, and shedding

The biodistribution and shedding of intralesionally administered talimogene laherparepvec were investigated in a clinical study that measured talimogene laherparepvec DNA in blood, urine, injection site, exterior of the occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. Sixty patients with melanoma received talimogene laherparepvec intralesional injection at a dose and schedule same as clinical study 005/05. Occlusive dressings samples were collected during treatment. Blood and urine samples were collected during treatment and for up to 30 days after the end of treatment. Injection site, oral mucosa, and anogenital area samples were collected during treatment and for up to 60 days after the end of treatment. Suspected herpetic lesion samples were collected any time a patient experienced lesions of suspected herpetic origin. If the qPCR testing for talimogene laherparepvec DNA was positive, then a TCID 50 assay was performed to measure viral infectivity. In the 60 patients treated, data indicate that talimogene laherparepvec DNA was present in all sites during the study (see table).

Patients with detectable DNA during treatment:

^a For the anogenital area, 26 patients were tested for talimogene laherparepvec DNA.

The proportion of samples and subjects with talimogene laherparepvec DNA was highest during cycle 2 of treatment for the blood, urine, injection site, and occlusive dressings; highest in cycle 1 of treatment for the oral mucosa; and highest in cycles 1 and 2 for the anogenital area. Among patients with detectable talimogene laherparepvec DNA in the blood, urine, oral mucosa, and anogenital area, no samples had detectable talimogene laherparepvec DNA 30 days after the end of treatment. For patients with detectable DNA in injected lesions, no samples had detectable talimogene laherparepvec DNA 60 days after end of treatment.

Overall 3 of 19 patients with lesions of suspected herpetic origin had talimogene laherparepvec DNA present at any time during the study. Viral activity was measured in samples that were positive for talimogene laherparepvec DNA from the injection site, occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. No viral activity was detected in samples of the occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. Infectious talimogene laherparepvec virus was detected at the site of injection in 7 (11%) patients at multiple time points in the study; no samples were positive for viral infectivity after cycle 2 or after the end of treatment.

Pharmacokinetics in special populations

No pharmacokinetic studies using talimogene laherparepvec have been conducted in special populations.

At doses up to 4 × 10⁸ PFU/kg or 10⁷ PFU/dose (60-fold over the highest proposed clinical dose), single or repeated doses of talimogene laherparepvec administered by SC, IV, or intratumoural injection were well tolerated in immunocompetent mice, rats, and dogs. No neuropathology or adverse neurological effects were observed. In an in vivo study of intracerebral injection, talimogene laherparepvec was 10,000-fold less neurovirulent as compared to the wild-type HSV-1 dose that results in death 50% of the time in mice.

Talimogene laherparepvec was injected into various xenograft tumours at doses up to 2 × 10⁸ PFU/kg (30-fold over the highest proposed clinical dose) in immunodeficient mice (nude and SCID). Lethal systemic viral infection was observed in up to 20% of nude mice (primarily deficient in T lymphocyte function) and 100% of SCID mice (devoid of both T and B lymphocytes).

Across studies, fatal disseminated viral infection was observed in 14% of nude mice following treatment with talimogene laherparepvec at doses that are 10 to 100-fold higher than those that result in 100% lethality with wild-type HSV-1.

Mutagenicity

The genotoxic potential of talimogene laherparepvec has not been evaluated in long-term animal or human studies. Because wild-type HSV-1 does not integrate into the host genome, the risk of insertional mutagenesis with talimogene laherparepvec is negligible.

Carcinogenicity

The carcinogenic potential of talimogene laherparepvec has not been evaluated in long-term animal or human studies. However, available data for talimogene laherparepvec and wild-type HSV-1 do not indicate a carcinogenic risk in humans.

Reproductive and development toxicity

There were no impacts to male or female reproductive tissues following treatment of adult mice at doses up to 4 × 10⁸ PFU/kg (60-fold higher, on a PFU/kg basis, compared to the maximum clinical dose). No effects on embryo-foetal development were observed when talimogene laherparepvec was administered during organogenesis to pregnant mice at doses up to 4 × 10⁸ (400 million) PFU/kg (60-fold higher, on a PFU/kg basis, compared to the maximum clinical dose). Negligible amounts (<0.001% of maternal blood levels) of talimogene laherparepvec DNA were found in foetal blood.