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.

Figure 1

Schematic showing the engineering of Talimogene laherparepvec (T-VEC). The backbone is the JS17 strain of herpes Simplex virus, type 1 in which the two viral ICP34.5 genes have been deleted and replaced with copies of the human GM-CSF genes under control of a CMV promoter. In addition, the viral ICP47 gene is deleted transitioning the viral US11 gene to an immediate-early promoter. The implications of these genetic modifications are listed in the box. Abbreviations: CMV, cytomegalovirus; hGM-CSF, human granulocyte-macrophage colony-stimulating factor; ICP, infected cell protein; IRL, long inverted repeat region; pA, polyadenylation tail; TR_L, long terminal repeat; TR_S, short terminal repeat; U_L, unique long region; U_S, unique short region; US11, unique short sequence 11.

Figure 2

Photograph of a melanoma patient (A) before; (B) 6 months after starting treatment with Talimogene laherparepvec (T-VEC); and (C) 9 months after starting treatment. The patient had multiple cutaneous and soft tissue metastases following amputation of a left great toe melanoma and failing systemic chemotherapy. A biopsy at 9 months confirmed the absence of viable melanoma cells.