Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers

Abstract

Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.

Keywords: immunotherapy; melanoma; oncolytic viruses; skin cancer; talimogene laherparepvec (T-VEC).

Figure 1

The dual anti-tumor mechanism of action of T-VEC. Initially, T-VEC infects tumor cells and replicates intracellularly, causing cell lysis and the release of TDAs. In addition to the local inflammation, the genetically-induced production of GM-CSF attracts and activates dendritic cells, which uptake the TDAs and activate CD4+ and CD8+ T cells, initiating a systemic anti-tumor response. T-VEC = Talimogene laherparepvec; TDAs = tumor-derived antigens; GM-CSF = granulocyte-macrophage colony-stimulating factor.