Abstract After decades of research, oncolytic viruses have finally demonstrated clinical efficacy against human tumors. Talimogene laherparepvec is a first-in-class, injectable oncolytic virus derived from herpes simplex virus (HSV) type 1. In talimogene laherparepvec, the HSV-1 is modified through deletion of two non-essential viral genes. Deletion of the neurovirulence factor genes (ICP34.5) leads to preferential replication of the virus in tumor cells as compared with normal cells, while deletion of the ICP47 gene is designed to reduce virus-mediated suppression of antigen presentation. In addition, insertion of a GM-CSF cassette induces local GM-CSF production and is intended to recruit and activate antigen-presenting cells, ultimately stimulating systemic tumor-specific T-cell responses. Directly administered into accessible lesions, talimogene laherparepvec is therefore designed to have a dual mechanism of action, namely tumor lysis of injected lesions and the induction of a systemic antitumor immune response. In a randomized, phase III trial comparing talimogene laherparepvec therapy with subcutaneously administered GM-CSF in patients with injectable melanoma that was not surgically resectable, the durable response rate (objective response lasting continuously ≥ 6 months) was 16.3% in patients receiving talimogene laherparepvec and 2.1% in those receiving GM-CSF (1). However, the mechanism by which talimogene laherparepvec may induce responses in uninjected, distant lesions has not been fully elucidated. To investigate this question, we conducted preclinical experiments using various syngeneic models in which both injected and uninjected tumors in a single mouse could be evaluated. These studies indicated that, as anticipated, a high proportion of lesions that were directly injected with OncoVexmGM-CSF, an HSV-1 modified similarly to talimogene laherparepvec except that murine GM-CSF is used in lieu of human GM-CSF, underwent complete regression. A proportion of distant, uninjected tumors also regressed, and these lesions demonstrated significant immune cell infiltrates, with efficacy dependent on the generation of systemic antitumor CD8-positive T cells. There was no evidence of viral replication in any distant tumors, consistent with findings from other preclinical models. Ongoing biomarker studies in clinical trials are intended to confirm and extend these findings, including investigation of potential markers of response or resistance to talimogene laherparepvec monotherapy. In addition to its use as a single agent, there is interest in combining talimogene laherparepvec with other immunotherapeutic agents. Preclinical experiments using tumor cell lines both susceptible and resistant to talimogene laherparepvec monotherapy suggest that the addition of either anti-CTLA-4 or anti-PD-1 antibodies significantly increases the proportion of mice that are “cured.” Preliminary data from early-phase clinical trials in advanced melanoma demonstrate that talimogene laherparepvec can be safely combined with ipilimumab or pembrolizumab, with evidence of antitumor effect, including complete responses. A randomized, double-blind phase III trial of talimogene laherparepvec in combination with either pembrolizumab or placebo in patients with advanced melanoma is actively recruiting patients and will provide significant insight into the effectiveness of this combination. Based on its mechanism of action, talimogene laherparepvec may have utility in tumor types beyond melanoma. An ongoing phase I trial is examining the safety of talimogene laherparepvec when injected into hepatic metastases of various solid tumors, and, once an acceptable safety profile has been demonstrated and a dose established, combination trials with checkpoint inhibitors are planned. One key question is whether tumors that are generally resistant to checkpoint inhibition can be rendered sensitive with the addition of talimogene laherparepvec.
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Dec 1, 2016
Xin-Tian Li + 6
Open Access
