Toxicity studies in thymidine kinase-deficient herpes simplex virus therapy for malignant astrocytoma
1Department of Surgery, University of British Columbia, Vancouver, Canada.
Abstract:
Previous studies have shown that genetically engineered thymidine kinase (tk)-defective herpes simplex virus type 1 (HSV-1) can effectively and selectively destroy gliomas in animal models. The consequences of viral infection and tumor regression must be characterized before this therapy can be applied in human trials. To study the potential for long-term toxicity, immunocompetent rats harboring 9L gliosarcomas were injected intratumorally with a tk-defective HSV-1, KOS-SB, at titers that previously have been demonstrated to cause tumor regression. In animals surviving 3 months or longer following viral treatment, there was no evidence of persistent infection or inflammation in peritumoral brain tissue or in remote systemic organs studied with routine histological and immunocytochemical analyses. Polymerase chain reaction using primers specific for HSV-1 detected HSV-1 DNA in peritumoral tissue only in animals sacrificed within 3 months of viral injection. There was no evidence of HSV-1 DNA in systemic tissues at any time after treatment. We conclude that stereotactic intratumoral injection of tk-deficient HSV can be attempted for the treatment of brain tumors without risk of systemic infection or significant toxicity to normal brain or remote proliferating tissues.
Insights
Genetically engineered herpes simplex virus type 1 (HSV-1) effectively targets gliomas. Long-term studies show this tk-defective HSV-1 treatment poses no significant risk of systemic infection or toxicity to healthy tissues.
Area of Science:
- Oncolytic virology
- Neuro-oncology
- Viral gene therapy
Background:
- Genetically engineered herpes simplex virus type 1 (HSV-1) demonstrates potential for selective glioma destruction in preclinical models.
- Characterizing the long-term consequences of viral infection and tumor regression is crucial for clinical translation.
Purpose of the Study:
- To evaluate the potential for long-term toxicity and systemic infection following intratumoral administration of a thymidine kinase (tk)-defective HSV-1 (KOS-SB) in a rat glioma model.
Main Methods:
- Immunocompetent rats with 9L gliosarcomas received intratumoral injections of tk-defective HSV-1 (KOS-SB).
- Histological, immunocytochemical, and polymerase chain reaction (PCR) analyses were performed on peritumoral brain tissue and systemic organs of surviving animals at various time points.
Main Results:
- No evidence of persistent HSV-1 infection or inflammation was found in peritumoral brain or systemic tissues of animals surviving 3 months or longer.
- HSV-1 DNA was detected in peritumoral tissue only in animals sacrificed within 3 months of injection, and not in any systemic tissues.
Conclusions:
- Stereotactic intratumoral injection of tk-deficient HSV-1 is a potentially safe approach for brain tumor treatment.
- This oncolytic viral therapy is associated with no risk of systemic infection or significant toxicity to normal brain or remote tissues.
