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Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer
1Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Nagoya, Japan.
Abstract:
Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. We have developed replication-competent attenuated herpes simplex virus type 1 (HSV-1) mutants, named HF10 and Hh101, which have been evaluated for their oncolytic activities. However, the host immune system remains a significant obstacle to effective intraperitoneal administration of these viruses in the clinical setting. In this study, we investigated the use of these HSV-1 mutants as oncolytic agents against ovarian cancer and the use of human peritoneal mesothelial cells (MCs) as carrier cells for intraperitoneal therapy. MCs were efficiently infected with HSV-1 mutants, and MCs loaded with HSV-1 mutants caused cell killing adequately when cocultured with cancer cells in the presence or absence of HSV antibodies. In a mouse xenograft model of ovarian cancer, the injection of infected carrier cells led to a significant reduction of tumor volume and prolonged survival in comparison with the injection of virus alone. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on ovarian cancer, which may be further enhanced by the utilization of a carrier cell delivery system, based on amplification of viral load and possibly on avoidance of neutralizing antibodies.
Insights
Replication-competent attenuated herpes simplex virus type 1 (HSV-1) effectively targets ovarian cancer. Using human peritoneal mesothelial cells as carriers enhances this oncolytic virus therapy, reducing tumor volume and improving survival in mice.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Oncolytic viruses show promise for cancer treatment through tumor-selective replication and lysis.
- Replication-competent attenuated herpes simplex virus type 1 (HSV-1) mutants (HF10, Hh101) have demonstrated oncolytic potential.
- The host immune response presents a challenge for effective intraperitoneal viral therapy.
Purpose of the Study:
- To evaluate HSV-1 mutants as oncolytic agents against ovarian cancer.
- To investigate human peritoneal mesothelial cells (MCs) as carrier cells for intraperitoneal oncolytic virus delivery.
Main Methods:
- Infection of human peritoneal mesothelial cells (MCs) with attenuated HSV-1 mutants.
- In vitro co-culture assays of infected MCs with ovarian cancer cells.
- In vivo evaluation in a mouse xenograft model of ovarian cancer using infected carrier cells versus virus alone.
Main Results:
- MCs were efficiently infected with HSV-1 mutants.
- MCs loaded with HSV-1 mutants effectively killed ovarian cancer cells in vitro, even with HSV antibodies present.
- Injection of infected MCs significantly reduced tumor volume and prolonged survival in a mouse model compared to virus injection alone.
Conclusions:
- Replication-competent attenuated HSV-1 demonstrates potent oncolytic activity against ovarian cancer.
- Utilizing MCs as a carrier cell delivery system can enhance oncolytic virotherapy by amplifying viral load and potentially evading neutralizing antibodies.
