Research Progress and Development Potential of Oncolytic Vaccinia Virus
Authors: Xinyu Zhang1,2,3, Jiangshan He1,2,3, Yiming Shao1,2,3
Affiliations:
- Changping Laboratory, Beijing 102206, China
- College of Life Science, Beijing Normal University, Beijing 100875, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
Abstract
Oncolytic virotherapy is a promising approach for cancer treatment, where oncolytic viruses (OVs) selectively infect and lyse tumor cells while triggering anti-tumor immune responses. Vaccinia virus (VV) has emerged as a leading candidate for oncolytic therapy due to its broad cytophilicity and robust capacity to express exogenous genes. This review provides an overview of the strategies used in developing oncolytic vaccinia virus (OVV), summarizes clinical trial findings, and discusses the challenges and future directions for enhancing OVV-based therapies. The goal is to improve tumor treatment outcomes and facilitate the clinical adoption of OVV.
Introduction
Oncolytic virotherapy (OVT) involves the use of viruses that selectively replicate within tumor cells, exerting viral cytotoxicity while sparing normal cells. The concept dates back to the 19th century, with early observations of tumor regression following viral infections. Modern advancements in genetic engineering and immunotherapy have renewed interest in OVT, particularly with the development of genetically modified OVs. Vaccinia virus (VV) has gained attention due to its large genome, ability to express exogenous genes, and safety profile.
Mechanisms of Action of Oncolytic Viruses
The primary mechanism of OVs is the lysis of tumor cells through viral replication, which releases tumor antigens and triggers systemic anti-tumor immune responses. OVs can also be engineered to express immune-stimulatory cytokines or immune checkpoint inhibitors, enhancing their anti-tumor efficacy. Additionally, OVs can target tumor vasculature, disrupting the blood supply to tumors and inducing cell death.
Vaccinia Virus as an Oncolytic Virus
Characterization of VV
VV is a large, double-stranded DNA virus with a genome exceeding 190 kb. Its life cycle occurs entirely in the cytoplasm, making it safer than other viral vectors. VV exists in three forms: intracellular mature virus particles (IMVs), cell-associated enveloped virus particles (CEVs), and extracellular enveloped virus particles (EEVs). Its broad cytotropism and ability to replicate in hypoxic conditions make it suitable for tumor targeting.
Modification Strategies for VV
To enhance its oncolytic potential, VV has been genetically modified to increase tumor selectivity and reduce virulence. Common strategies include the deletion of the thymidine kinase (TK) gene, which restricts replication to tumor cells, and the insertion of genes encoding cytokines or immune checkpoint inhibitors. Other modifications involve the deletion of virulence-related genes to improve safety and efficacy.
Clinical Progress in OVV
Several OVVs have entered clinical trials, with JX-594 and GL-ONC1 being the most advanced. JX-594, a TK-deleted VV expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), has shown promise in treating hepatocellular carcinoma. GL-ONC1, another TK-deleted VV, has demonstrated efficacy in ovarian cancer and head and neck cancer. Despite some setbacks in Phase III trials, these OVVs have shown potential in enhancing anti-tumor immunity and overcoming chemoresistance.
Challenges and Future Directions
Immune Clearance and Safety
One major challenge is the immune system’s ability to clear OVVs, limiting their efficacy. Strategies to evade immune clearance include encapsulation in nanoparticles or the use of cellular vectors. Ensuring the safety of OVV therapy is also critical, as unintended infection of normal cells can cause adverse effects. Suicide gene systems, such as HSV-TK/GCV, have been explored to control OVV replication and enhance safety.
Enhancing Anti-Tumor Efficacy
Combining OVV with other therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, has shown synergistic effects. Future research should focus on optimizing these combinations and exploring novel strategies, such as metabolic reprogramming and gene therapy, to enhance OVV efficacy.
Targeting Specific Tumors
Different tumors exhibit varying sensitivities to OVVs, highlighting the need for personalized approaches. Understanding the mechanisms underlying tumor resistance and developing OVVs tailored to specific tumor types will be crucial for improving clinical outcomes.
Conclusion
Oncolytic vaccinia virus represents a promising approach to cancer treatment, with the potential to selectively target and destroy tumor cells while triggering robust anti-tumor immune responses. Despite challenges, advancements in genetic engineering and combination therapies continue to enhance the efficacy and safety of OVV. Future research should focus on optimizing OVV design, understanding tumor-specific mechanisms, and developing personalized treatment strategies to realize the full potential of oncolytic virotherapy.
DOI: 10.1097/CM9.0000000000003585
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