Abstract
Simple SummaryTalimogene laherparepvec (T-VEC), a first-in-class oncolytic herpes simplex virus, improves the outcome of patients suffering from unresectable melanoma, in particular in combination with checkpoint inhibitors. However, a certain percentage of patients does not profit from this treatment, which raises the question of potential biomarkers to predict success or failure of oncolytic herpes viruses. For these purposes, we studied the oncolytic activity of T-VEC in a panel of 20 melanoma cell lines and evaluated the clinical response of 35 melanoma metastases to intralesional T-VEC application. Through these studies, we characterized Nectin-1 as a suitable biomarker predicting 86% and 78% of melanoma regression in vitro and in vivo, respectively. In contrast, other molecules involved in the entry (HVEM) and signal transduction (cGAS, STING) of herpes simplex viruses were not predictive. Altogether, our data support the role of Nectin-1 in pretreatment biopsies to guide clinical decision-making in malignant melanoma and supposedly other tumor entities.Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.
Highlights
Talimogene laherparepvec (T-VEC) is a genetically modified and thereby attenuated herpes simplex virus type 1 (HSV-1) derived from the JS1 strain [1]
In puromycin-selected bulk culAfter plating a panel of 20 melanoma cell lines into 96-well plates, 10,000 cells/well were tures, Nectin-1 was knocked out in Nectin-1-KO and Nectin-1-/herpes virus entry mediator (HVEM)-double KO cells, infected with the oncolytic HSV-1 strain T-VEC (MOI 1)
The in vitro data of our study are based on MTT metabolic activity and lactate dehydrogenase (LDH) release of malignant melanoma cell lines 48 h post T-VEC inoculation
Summary
Talimogene laherparepvec (T-VEC) is a genetically modified and thereby attenuated herpes simplex virus type 1 (HSV-1) derived from the JS1 strain [1]. Deletion of neurovirulence factor infected cell protein (ICP) 34.5 provides tumor selectivity and impedes replication in neuronal cells [2], while deletion of ICP47 restores the activity of transporter associated with antigen processing [3,4]. The latter promotes loading of HSV-1 and tumor peptides onto MHC I, which supports recognition and oncolysis of infected tumor tissue by CD8+ T cells. In a randomized phase III trial of intratumoral T-VEC versus GM-CSF injection in unresectable stage III/IV melanoma (OPTiM trial), 19.3% (n = 57) of patients treated with
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