Talimogene Laherparepvec for the Treatment of Advanced Melanoma

Abstract

Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an "in situ vaccine" effect. Based on an increased durable response rate compared with granulocyte macrophagecolony stimulating factor in a randomized phase III trial, it was approved by the FDA for the treatment of melanoma metastatic to skin or lymph nodes. The drug is currently in clinical trials as monotherapy and in combination with immune-checkpoint inhibitors and radiotherapy in melanoma and other cancers. The mechanism of action, toxicity, and efficacy as well as its role in current clinical practice and potential future applications are reviewed.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…For such visible lesions, regression of the injected tumours was reproducibly demonstrated. Unlike with other injectable agents, responses to T-VEC were observed in adjacent uninjected lesions, and occasionally at distant metastases 96,98 .…”

“…The most recently approved agent for the treatment of patients with advanced-stage, unresectable melanoma is T-VEC, an injectable modified herpes virus genetically engineered to selectively replicate in tumour cells, and to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) 96 . The virus itself is known to elicit immune responses and, when incorporated into tumour cells, induces tumour-specific production and secretion of GM-CSF, which independently enhances antigen presentation by tissue-resident macrophages 97 .…”

Oncolytic herpes simplex virus interactions with the host immune system

“…For cancer therapy in immmunocompetent models, oHSV acts as an in situ vaccine, with T-cells playing a critical role as immune cell mediators of efficacy [2,77]. Both in mice and T-Vec melanoma responders, oHSV treatment led to a reduction in Tregs [77,78]. In the T-Vec phase III clinical trial durable responses were observed not only in injected lesions, but also non-injected, with 11% of patients having complete responses, strongly suggestive of robust immune responses [1,78*].…”

“…Both in mice and T-Vec melanoma responders, oHSV treatment led to a reduction in Tregs [77,78]. In the T-Vec phase III clinical trial durable responses were observed not only in injected lesions, but also non-injected, with 11% of patients having complete responses, strongly suggestive of robust immune responses [1,78*]. Augmenting this with immune modulators like immune checkpoint inhibitors or expression of immune modulatory transgenes like IL-12 is actively being pursued [3,77,78].…”

“…An enveloped virus with a 152 kb DNA genome, HSV-1 is a human pathogen that is endowed with oncolytic activity by mutating non-essential genes involved in virus growth in post-mitotic cells (i.e., thymidine kinase, ribonucleotide reductase (ICP6)), counteracting innate anti-viral responses (i.e., γ34.5, ICP0, Us3) and pathogenicity (i.e., γ34.5, UL56, ribonucleotide reductase (ICP6)) [3]. In 2015, the FDA approved the first OV, an oncolytic HSV (oHSV), talimogene laherparepvec (T-VEC, Imlygic), for advanced melanoma [4]. Cancer treatment with oHSV, like other OVs, induces a variety of immune and inflammatory responses, both beneficial and detrimental.…”