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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV-tk
1Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1851, USA.
Abstract:
Currently available therapeutic modalities for advanced head and neck squamous cell carcinoma (HNSCC), such as radical surgery, high-dose radiotherapy, and chemotherapy, are of limited efficacy. Overall survival has not significantly improved over the past 30 years; thus, HNSCC represents a promising target for new therapeutic approaches, such as gene therapy. A major obstacle to the development of effective suicide gene therapy strategies that rely on in situ transduction of tumor cells is the poor distribution of the vector throughout the tumor. To address this problem we evaluated the use of Ad.OW34, an Elb 55 kD and HSV-tk-carrying, replication-competent adenoviral vector that has a wild-type adenovirus phenotype in replicating cells, in combination with ganciclovir (GCV) as a treatment for HNSCC xenografts in nude mice and compared its efficacy with that of a standard replication-deficient adenovirus expressing HSV-tk (Ad.TK). In this model, Ad.OW34 had a significantly greater antitumor effect than the traditional Ad.TK vector, administered alone or in combination with GCV. Interestingly, GCV did not further enhance the oncolytic efficacy of Ad.OW34. GCV also aborts viral replication and thus represents a fail-safe feature of this vector not found in wild-type adenovirus.
Insights
A novel gene therapy using a replication-competent adenoviral vector (Ad.OW34) shows superior antitumor effects against head and neck squamous cell carcinoma (HNSCC) in mice compared to traditional methods. Ganciclovir (GCV) did not enhance efficacy but provided a safety feature.
Area of Science:
- Oncolytic virotherapy
- Gene therapy for cancer
- Head and neck cancer research
Background:
- Advanced head and neck squamous cell carcinoma (HNSCC) has limited treatment options with poor survival rates.
- Gene therapy, specifically suicide gene therapy, offers a promising avenue for HNSCC treatment.
- Poor vector distribution in tumors is a major challenge for in situ gene therapy.
Purpose of the Study:
- To evaluate the efficacy of a replication-competent adenoviral vector (Ad.OW34) carrying Elb 55 kD and HSV-tk genes for HNSCC treatment.
- To compare Ad.OW34's antitumor effect with a standard replication-deficient adenovirus expressing HSV-tk (Ad.TK).
- To assess the impact of ganciclovir (GCV) on Ad.OW34 efficacy and safety.
Main Methods:
- Utilized a nude mouse xenograft model of HNSCC.
- Administered Ad.OW34 (replication-competent, Elb 55 kD, HSV-tk) and Ad.TK (replication-deficient, HSV-tk) with and without ganciclovir (GCV).
- Compared antitumor effects and viral replication characteristics.
Main Results:
- Ad.OW34 demonstrated significantly greater antitumor efficacy than Ad.TK in the HNSCC xenograft model.
- Ganciclovir (GCV) did not enhance the oncolytic efficacy of Ad.OW34.
- GCV served as a fail-safe mechanism by aborting viral replication, a feature absent in wild-type adenovirus.
Conclusions:
- Replication-competent adenoviral vectors like Ad.OW34 hold potential for improved HNSCC gene therapy.
- The combination of Ad.OW34 with GCV offers a potentially safer and more effective therapeutic strategy.
- Further research into optimizing vector delivery and replication control is warranted for clinical translation.
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