Oncolytic vaccinia virus and cancer immunotherapy

Abstract

Oncolytic virotherapy (OVT) is a promising form of cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger anti-tumor immune response. In addition to killing cancer cells, oncolytic viruses can also remodel the tumor microenvironment and stimulate a long-term anti-tumor immune response. Despite achieving positive results in cellular and organismal studies, there are currently only a few approved oncolytic viruses for clinical use. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs. The safety and efficacy of different viral backbones are explored, as well as the effects of oncolytic VACVs on the tumor microenvironment. The potential combination of oncolytic VACVs with immunotherapy or traditional therapies is also highlighted. The review concludes by addressing prospects and challenges in the field of oncolytic VACVs, with the aim of promoting further research and application in cancer therapy.

Keywords: cancer immunotherapy; combination therapy; oncolytic virotherapy; tumor microenvironment; vaccinia virus.

Figure 1

Anti-tumor mechanisms of oncolytic VACVs. Oncolytic VACVs can kill cancer cells via a variety of mechanisms. First, they directly infect, replicate and lyse tumor cells sparing normal cells. Released virions can infect neighbor tumor cells and so forth. Second, oncolytic VACVs can infect and lyse tumor associated vascular endothelial cells, meanwhile recruiting neutrophile cells and inducing thrombosis. Third, they can remodel the “cold” TME to “hot” by activating innate and adoptive anti-tumor immunity. The release of progeny viruses and PAMPs/DAMPs can promote the innate immune cells to produce proinflammatory cytokines and chemokines, which in turn lead to the recruitment and activation of more immune cells, thus innate immune responses are activated. With the activation of antigen presentation cells, DCs can present the released TAA/TAN to T-cells, enhancing the tumor recognition and killing ability of CD8⁺ T-cells, inducing a tumor-specific adoptive immune response. PAMPs, Pathogen-associated molecular patterns; DAMPs, Damage-associated molecular pattern; TAA, Tumor-associated antigens; TAN, Tumor-associated neoantigens; DC, Dendritic cell; NK cell, Natural killer cell. The figure is drawn by FigDraw.

Figure 2

Strategies for oncolytic VACV-based immune-related combination therapies. Strategies are divided into two main categories: genetic engineering of oncolytic VACVs and combination with other immunotherapies. In terms of genome engineering (left), various immunostimulatory genes can be inserted into the genome of oncolytic VACVs, including those can activate the anti-tumor immunity directly, improve the T-cells recognition to cancer cells, recruit and activate immune cells. In terms of synergistic immunotherapies (right), oncolytic VACVs can be combined with CAR T-cell or ICI molecules directly or express CAR or ICI to enhance the synergistic therapies. oncolytic VACV, Oncolytic vaccinia virus; TAA, Tumor associated antigen; BiTE, Bispecific T-cell engager; CAR, Chimeric antigen receptor; ICI, Immune checkpoint inhibitor; scFv, Single chain variable fragment. The figure is drawn by FigDraw.