Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy: a comprehensive review

Abstract

Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration. Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication; however, recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments. Specifically, oncolytic vaccinia virus (OVV) has gained popularity owing to its safety, potential for systemic delivery, and large gene insertion capacity. This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo, and provides an overview of ongoing clinical trials and combination therapies. In addition, we discuss the potential benefits and drawbacks of OVV as a cancer therapy, and explore different perspectives in this field.

Keywords: Oncolytic virotherapy; arming strategy; engineered virus; oncolytic vaccinia virus.

Figure 1

The life cycle of VV and major viral proteins involved in virus formation and transmission. The virus forms a fusion protein complex that consists of eight viral proteins (A16, A21, A28, G3, G9, H2, J5, and L5), then enters the cell interior. IMV, as an infectious form, has A17L, A27L, and D8L to help adhere to the surface of the cell membrane. VV replication and progeny assembly occur in the “poxvirus factory” of the cytoplasm of infected cells. IMV is transported to the extracellular space through microtubules, while fusing with the cell membrane to form CEV. CEV encodes genes (A33R, A34R, A36R, A56R, B5R, and F13L), thus forming EEV for intercellular transmission and distant metastasis. IMV can also be encapsulated by the Golgi complex to form IEV, which is then transported to the periphery of cells mediated by F12L and A36R. IMV, intracellular mature virus; CEV, cell-associated enveloped virus; EEV, extracellular enveloped virus; IEV, intracellular enveloped virus.

Figure 2

Scheme of engineered oncolytic vaccinia virus (OVV) and mechanisms of enhanced anti-tumor activity. OVVs armed with cytokines or tumor suppressor genes enhance immune cell infiltration, damage the vascular bed, inhibit suppressive immune cells (such as MDSCs and Tregs), and induce cell apoptosis and autophagy, thus resulting in the release of tumor-associated antigens. OVVs express immunotherapeutic genes, including those encoding immune checkpoint inhibitors, antibodies, and bispecific antibodies, which exert potent and specific cytotoxicity in a variety of tumor models by enhancing immunotherapeutic effects. Modified OVVs with a thymidine kinase (TK) deletion, the insertion of a suicide gene, and expression of siRNA have increased oncolytic properties and safety.

Figure 3

Tumor microenvironment remodelling induced by OVV. The OVV can be administered intravenously, after which it selectively infects and replicates in tumor cells. OVV is then released within the tumor microenvironment (TME), resulting in a change in the TME from the original ‘cold’ state (immunosuppression) to a ‘hot’ state (immune activation) due to the infiltration of immune cells. Macrophages and dendritic cells engulf OVV-infected tumor cells and present antigens to lymphocytes. CD8+ T lymphocytes work in coordination with immune checkpoint inhibitors or immunotherapeutic antibodies released by OVV-infected tumor cells and eliminate the tumor cells. The armed antibody with an Fc fragment results in the activation of natural killer (NK) cells, thereby stimulating the antibody-dependent cellular cytotoxicity of NK cells. DAMPs, danger-associated molecular patterns; TAAs, tumor-associated antigens; Treg cells, regulatory T cells.