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Ovarian cancer gene therapy
D L Tait1, P S Obermiller, R A Jensen
1Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
Retroviral-mediated delivery of BRCA1 gene therapy (LXN-BRCA1sv, a normal splice variant form of BRCA1) was tested extensively in mouse models. It was found to be effective in reducing tumor burden and to be minimally toxic. Twelve phase I clinical trial patients with recurrent or persistent epithelial ovarian cancer were treated with one to three cycles of intraperitoneal vector. There was minimal toxicity, four patients developed fevers (< 102.5 degrees F) and three had sterile peritonitis, which resolved within 48 hours. The vector was found to be fairly stable in some patients at 24 hours as well as transferred into and expressed in patient tissues. Stable disease was noticed in 8 of the 12 patients, suggesting that the peritoneal cavity may be an appropriate site for gene therapy.
Insights
Gene therapy using LXN-BRCA1sv, a BRCA1 splice variant, effectively reduced ovarian cancer tumor burden in mice and showed minimal toxicity in human trials. The treatment demonstrated stability and expression in patients, with 8 of 12 achieving stable disease.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- BRCA1 gene mutations are linked to increased ovarian cancer risk.
- Retroviral vectors are being explored for targeted gene delivery in cancer therapy.
- LXN-BRCA1sv represents a normal splice variant of the BRCA1 gene for therapeutic use.
Purpose of the Study:
- To evaluate the efficacy and safety of retroviral-mediated BRCA1 gene therapy (LXN-BRCA1sv) in preclinical models and a Phase I clinical trial for ovarian cancer.
- To assess the vector's stability, tissue transfer, and expression in patients with recurrent or persistent epithelial ovarian cancer.
Main Methods:
- Preclinical testing in mouse models to assess tumor reduction and toxicity.
- Phase I clinical trial involving 12 patients with recurrent/persistent epithelial ovarian cancer receiving intraperitoneal LXN-BRCA1sv vector.
- Monitoring for toxicity, vector stability, gene expression, and clinical response (stable disease).
Main Results:
- LXN-BRCA1sv demonstrated significant tumor burden reduction and minimal toxicity in mouse models.
- In the Phase I trial, the gene therapy showed minimal toxicity, with manageable side effects like fever and sterile peritonitis.
- The vector exhibited stability and expression in patient tissues, with 8 out of 12 patients achieving stable disease.
Conclusions:
- The peritoneal cavity may be a suitable site for gene therapy delivery in ovarian cancer.
- Retroviral-mediated delivery of LXN-BRCA1sv is a potentially safe and effective therapeutic strategy for recurrent or persistent epithelial ovarian cancer.
- Further investigation into BRCA1 gene therapy for ovarian cancer is warranted based on these promising preliminary results.