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Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications
Hanni Uusi-Kerttula1, Sarah Hulin-Curtis2, James Davies3
1Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. uusi-kerttulahk@cardiff.ac.uk.
Abstract:
Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.
Insights
Adenovirus (Ad) therapies face challenges from immunity and targeting. Novel strategies like altered serotypes and immune activation are key for effective oncolytic virotherapy.
Area of Science:
- Oncolytic Virotherapy
- Gene Therapy
- Immunology
Background:
- Adenoviruses (Ad) are widely used in experimental and clinical settings, particularly for oncolytic virotherapy.
- High pre-existing neutralizing immunity (up to 90%) limits Ad efficacy by reducing bioavailability and tumor targeting.
- Ubiquitous Ad5 receptor (hCAR) expression and lack of tumor-specific ligands hinder active tumor targeting.
Purpose of the Study:
- To review recent advancements and challenges in adenoviral oncolytic therapies.
- To explore strategies for overcoming immune clearance and improving tumor targeting of adenoviral vectors.
- To discuss methods for enhancing the oncolytic potential and cancer-specific immune responses.
Main Methods:
- Review of current literature on adenoviral vector design and application.
- Analysis of strategies to evade humoral immune recognition (e.g., altered serotypes, capsid modifications).
- Examination of methods to enhance oncolytic activity via immunostimulatory agents.
Main Results:
- Strategies like using less common Ad serotypes, pseudotyping, and capsid modifications can improve immune escape.
- Incorporating immunostimulatory agents can enhance cancer-specific immune responses.
- Off-target interactions and dose-limiting toxicities remain significant challenges.
Conclusions:
- Novel strategies are crucial for overcoming Ad vector limitations in clinical applications.
- Modifying Ad vectors to escape immunity and target tumors selectively is essential for effective oncolytic virotherapy.
- Balancing vector evasion with targeted immune activation is key for future Ad-based cancer therapies.
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