Highly efficient gene transfer to solid tumors in vivo by tumor-selective replicating retrovirus vectors

Area of Science:

• Oncolytic virotherapy
• Cancer gene therapy
• Retroviral vector development

Background:

• Tumor-selective replicating viruses offer potential for cancer gene therapy but often provide only temporary tumor suppression.
• Replicating retrovirus vectors (RRVs) enable efficient, tumor-specific gene transduction and sustained transgene expression.

Purpose of the Study:

• To develop and evaluate RRVs encoding yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (TK) for enhanced cancer gene therapy.
• To assess the in vitro and in vivo therapeutic efficacy of RRV-mediated suicide gene therapy using prodrugs 5-fluorocytosine (5-FC) and ganciclovir (GCV).

Main Methods:

• Development of RRVs engineered to express yCD and TK suicide genes.
• In vitro and in vivo testing of RRV-mediated gene therapy in human breast cancer models (MDA-MB-435 xenografts).
• Administration of 5-FC and GCV prodrugs to activate suicide gene therapy.

Main Results:

• RRV-mediated expression of yCD and TK resulted in significantly enhanced cytotoxicity upon prodrug administration.
• Significant suppression of tumor growth was observed in subcutaneous human breast cancer xenograft models.
• No detectable systemic spread of the RRV vector to extratumoral tissues was observed.

Conclusions:

• RRVs facilitate efficient, tumor-selective, and stable gene integration for potent cancer gene therapy.
• The combination of RRVs with yCD/TK suicide genes and prodrugs offers a promising strategy for significant tumor growth suppression.
• This approach demonstrates a favorable safety profile with no detected off-target vector dissemination.