Engineering vaccinia virus as an immunotherapeutic battleship to overcome tumor heterogeneity

ABSTRACT

Introduction

Immunotherapy is a rapidly evolving area of cancer therapeutics aimed at driving a systemic immune response to fight cancer. Oncolytic viruses (OVs) are at the cutting-edge of innovation in the immunotherapy field. Successful OV platforms must be effective in reshaping the tumor microenvironment and controlling tumor burden, but also be highly specific to avoid off-target side effects. Large DNA viruses, like vaccinia virus (VACV), have a large coding capacity, enabling the encoding of multiple immunostimulatory transgenes to reshape the tumor immune microenvironment. VACV-based OVs have shown promising results in both pre-clinical and clinical studies, including safe and efficient intravenous delivery to metastatic tumors.

Area covered

This review summarizes attenuation strategies to generate a recombinant VACV with optimal tumor selectivity and immunogenicity. In addition, we discuss immunomodulatory transgenes that have been introduced into VACV and summarize their effectiveness in controlling tumor burden.

Expert opinion

VACV encodes several immunomodulatory genes which aid the virus in overcoming innate and adaptive immune responses. Strategic deletion of these virulence factors will enable an optimal balance between viral persistence and immunogenicity, robust tumor-specific expression of payloads and promotion of a systemic anti-cancer immune response. Rational selection of therapeutic transgenes will maximize the efficacy of OVs and their synergy in combinatorial immunotherapy schemes.

KEYWORDS:

• Vaccinia virus
• oncolytic virotherapy
• anti-tumor immunity
• transgene

Article highlights

• VACV has ideal oncolytic properties owing to its tumor selectivity, well-established safety profile, and large coding capacity for therapeutic transgenes.

• Oncolytic VACV strains have been optimized for tumor selectivity, persistence, and immunogenicity through a number of strategies, including genetic deletions, directed evolution and transgene incorporation.

• Secretion of virus-encoded immune modulators has the potential to leak into the vasculature and mediate adverse effects.

• Fusing antibodies and targeting motifs can mediate tumor-specific delivery of therapeutic payloads.

• Early studies examining combination immunotherapy of OVs with CAR T cells show promising synergy in the treatment of solid tumors.

This box summarizes key points contained in the article.

Acknowledgments

We apologize to the authors of the studies we omitted in this review due to space restrictions. Figures 2-4 were composed by Christine Kenney (http://ckenneyillustration.com/).

Declaration of interest

JC Bell is a founder of Turnstone Biologics. JC Bell was supported by the Canadian Cancer Society Research Institute, the Canadian Institutes of Health Research (CIHR), the Ontario Institute of Cancer Research, and the Terry Fox Foundation. R Singaravelu was supported by a CIHR Postdoctoral Fellowship and the CanPRIME Mitacs Accelerate program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.