Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma

Abstract

Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; Imlygic™), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. 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. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non-melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses.

Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: A report of 2 cases

“…It consists of a herpes simplex type 1 virus genetically modified to selectively replicate in tumor cells and express human granulocyte-macrophage colony-stimulating factor to activate dendritic cells for antigen presentation 19 . Viral infection causes release of pro-inflammatory and danger-associated molecules including viral and cellular DNA which, induce innate immunity, host interferon response, and T-cell infiltration of the tumor microenvironment 20 . Dying tumor cells may release soluble antigens or be engulfed by antigen-presenting cells to prime tumor-specific T cells, which can destroy uninfected tumors at distant sites.…”

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines

“…Third, immunosuppressive cells such as Tregs and myeloid derived suppressive cells (MDSCs) tend to accumulate with tumor progression facilitating tumor escape and T cell exhaustion. Hence, it seems that there is a loosely defined, narrow window of opportunity, after tumor onset but before significant progression, where therapeutic tumor vaccines may yield maximum benefit [36]. Chemotherapy and immunotherapeutics that actively neutralize specific immune-suppressive factions such as Tregs (cyclophosphamide), T cell anergy (checkpoint inhibitors), suppressive cytokines (neutralizing antibodies) and MDSCs (signaling inhibitors) [63,64] need to be co-administered with cancer vaccines to unleash the immune components and allow the vaccines to engage the entire arsenal of immune cells to overcome the tumor [32].…”

“…Attenuated herpes simplex virus (HSV) engineered to express human GM-CSF, Talimogene laherparepvec (TVec), is the first FDA approved virotherapy used in humans. TVec is administered intratumoraly and is found to be maximally effective in early stages of melanoma (NCT00769704) [36]. Currently, TVec is being evaluated in combination with checkpoint blockade drugs (NCT01740297).…”

The renaissance of anti‐neoplastic immunity from tumor cell demise

“…Oncolytic viral therapies exert immune‐promoting effects through at least two mechanisms: (i) viral replication‐induced cancer cell death, which facilitates tumor antigen exposure and cross‐presentation; (ii) the accumulation of local immune cells and immunostimulatory molecules triggered by cell death and infection . A genetically modified HSV1716 encoding GM‐CSF (T‐VEC) demonstrated a significant improvement in durable response rates by facilitating DC expansion, antigen presentation, and T‐cell priming . Local oncolytic virotherapy can sensitize poorly immunogenic tumors to immune checkpoint blockade, resulting in rejection of distant tumors.…”