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Review
. 2021 Apr 27:5:PO.21.00003.
doi: 10.1200/PO.21.00003. eCollection 2021.

Strategies to Develop Potent Oncolytic Viruses and Enhance Their Therapeutic Efficacy

Omeed Moaven  1 , Christopher W Mangieri  2 , John A Stauffer  1 , Panos Z Anastasiadis  3 , Mitesh J Borad  4
Affiliations
Review

Strategies to Develop Potent Oncolytic Viruses and Enhance Their Therapeutic Efficacy

Omeed Moaven et al. JCO Precis Oncol. .

Abstract

Despite advancements in cancer therapy that have occurred over the past several decades, successful treatment of advanced malignancies remains elusive. Substantial resources and significant efforts have been directed toward the development of novel therapeutic modalities to improve patient outcomes. Oncolytic viruses (OVs) are emerging tools with unique characteristics that have attracted great interest in developing effective anticancer treatment. The original attraction was directed toward selective replication and cell-specific toxicity, two unique features that are either inherent to the virus or could be conferred by genetic engineering. However, recent advancements in the knowledge and understanding of OVs are shifting the therapeutic paradigm toward a greater focus on their immunomodulatory role. Nonetheless, there are still significant obstacles that remain to be overcome to enhance the efficiency of OVs as effective therapeutic modalities and potentially establish them as part of standard treatment regimens. In this review, we discuss advances in the design of OVs, strategies to enhance their therapeutic efficacy, functional translation into the clinical settings, and various obstacles that are still encountered in the efforts to establish them as effective anticancer treatments.

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Conflict of interest statement

Mitesh J. Borad Stock and Other Ownership Interests: Gilead Sciences, Aveo, Intercept Pharmaceuticals, Spectrum Pharmaceuticals Consulting or Advisory Role: G1 Therapeutics, Fujifilm, Agios, Insys Therapeutics, Novartis, ArQule, Celgene, Inspyr Therapeutics, Halozyme, Pieris Pharmaceuticals, Taiho Pharmaceutical, Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, Imvax Research Funding: Boston Biomedical, miRNA Therapeutics, Senhwa Biosciences, MedImmune, BiolineRx, Agios, Halozyme, Celgene, Threshold Pharmaceuticals, Toray Industries, Dicerna, Sillajen, Eisai, Taiho Pharmaceutical, EMD Serono, Isis Pharmaceuticals, Incyte, Sun Biopharma, ARIAD, ImClone Systems, QED Therapeutics, Puma Biotechnology, Adaptimmune, Merck Serono, RedHill Biopharma, Basilea Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca No other potential conflicts of interest were reported.Mitesh J. Borad Stock and Other Ownership Interests: Gilead Sciences, Aveo, Intercept Pharmaceuticals, Spectrum Pharmaceuticals Consulting or Advisory Role: G1 Therapeutics, Fujifilm, Agios, Insys Therapeutics, Novartis, ArQule, Celgene, Inspyr Therapeutics, Halozyme, Pieris Pharmaceuticals, Taiho Pharmaceutical, Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, Imvax Research Funding: Boston Biomedical, miRNA Therapeutics, Senhwa Biosciences, MedImmune, BiolineRx, Agios, Halozyme, Celgene, Threshold Pharmaceuticals, Toray Industries, Dicerna, Sillajen, Eisai, Taiho Pharmaceutical, EMD Serono, Isis Pharmaceuticals, Incyte, Sun Biopharma, ARIAD, ImClone Systems, QED Therapeutics, Puma Biotechnology, Adaptimmune, Merck Serono, RedHill Biopharma, Basilea Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Mechanisms of therapeutic anticancer effects of OV. OVs selectively infect cancer cells and use host cellular apparatus to replicate and directly lyse the tumor cells. This will release replicated viral progeny to reinfect adjacent tumor cells, and this cycle continues. In addition, lysis of tumor cells (oncolysis) initiates a cascade of events that leads to ICD, mediated by releasing DAMP, PAMP, and TAA and induces a pro-inflammatory state by an increase in the production of various cytokines and chemokines. An increase in chemokines such as CXCL9, CXCL10, and CXCL11 will enhance T-cell trafficking and infiltration into the TME. Release of various DAMPs (eg, HSPs, HMGB1, and calreticulin), PAMP (viral DNA, capsid, and proteins), and TAAs will promote DC maturation, further production of interferons, and enhancement of T-cell priming. Promoting antigen presentation via APCs and associated MHC I and MHC II upregulation will further enhance tumor recognition. Collectively, the pro-inflammatory state, mediated by various cytokines and chemokines, inhibits the TME immunosuppression, which is promoted by regulating the composition of the TME through various mechanisms such as suppressing cancer-associated fibroblasts and phenotypic conversion of immunosuppressive macrophages. The innate immune system can also be enhanced by direct activation of NK cells and subsequent antitumor cytotoxicity. APC, antigen-presenting cell; DAMP, damage-associated molecular patterns; DC, dendritic cell; HMGB1, high-mobility group box 1; HSP, heat shock protein; ICD, immunogenic cell death; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; NK cell, natural killer cell; OV, oncolytic virus; PAMP, pathogen-associated molecular patterns; TAA, tumor-associated antigen; TME, tumor microenvironment; TNF, tumor necrosis factor.
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