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Comparison of Liver Detargeting Strategies for Systemic Therapy with Oncolytic Adenovirus Serotype 5
Tien V Nguyen1, Mary E Barry2, Mallory A Turner3
1Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology and Biodefense Program, Mayo Clinic, Rochester, MN 55902, USA. nguyen.tien@mayo.edu.
Abstract:
Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, (3) chemical shielding, or (4) by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5) in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-dl1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-dl1101/07 was next chemically shielded with polyethylene glycol (PEG). While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-dl1101/07, this shielding reduced Ad oncolytic activity.
Insights
Harnessing oncolytic adenoviruses for systemic cancer therapy requires enhanced specificity. Physically detargeting adenovirus serotype 5 improved efficacy in treating disseminated tumors.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Immunology
Background:
- Oncolytic viruses offer potential for systemic cancer treatment, but require enhanced safety and specificity.
- Adenovirus serotype 5 (Ad5) is a candidate for oncolytic virotherapy, with strategies to modify its targeting and replication.
- Developing multi-layered cancer specificity is crucial for safe and effective systemic delivery.
Purpose of the Study:
- To evaluate different strategies for enhancing the specificity and efficacy of oncolytic adenovirus serotype 5 (Ad5) for systemic cancer therapy.
- To compare the effectiveness of physical detargeting and conditional replication in immunocompetent hamsters with disseminated tumors.
- To assess the impact of chemical shielding on Ad5-mediated oncolysis and immune response.
Main Methods:
- Utilized physically hepatocyte-detargeted Ad5-hexon-BAP and conditionally replicating Ad5-dl1101/07 in Syrian hamsters with subcutaneous HaK tumors.
- Administered viruses intravenously to assess systemic delivery and intratumorally for secondary treatment efficacy.
- Chemically shielded Ad5-dl1101/07 with polyethylene glycol (PEG) to evaluate its effect on pro-inflammatory cytokine production and oncolytic activity.
Main Results:
- The physically hepatocyte-detargeted virus Ad5-hexon-BAP demonstrated greater efficacy than conditionally replicating Ad5-dl1101/07 after intravenous injection.
- Prior Ad5 exposure did not influence tumor growth during secondary intratumoral treatment, indicating no significant impact of anti-Ad immunity on efficacy or anti-tumor responses.
- Polyethylene glycol (PEG) shielding of Ad5-dl1101/07 reduced interleukin-6 (IL-6) production but also diminished its oncolytic activity.
Conclusions:
- Physical detargeting of oncolytic adenovirus serotype 5 represents a promising strategy for improving systemic delivery and efficacy against disseminated cancers.
- Conditional replication, while a safety mechanism, was less effective than physical detargeting in this model.
- Chemical shielding with PEG can modulate the inflammatory response but may compromise the therapeutic oncolytic effect of adenoviruses.
