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Carcinoembryonic antigen directed herpes viral oncolysis improves selectivity and activity in colorectal cancer
Maura Reinblatt1, Richard H Pin, Yuman Fong
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Background:
G207 is an oncolytic herpes virus whose replicative cycle requires cellular ribonucleotide reductase (RR) for viral DNA synthesis. We attempt to enhance viral cytotoxicity in carcinoembryonic antigen (CEA)-producing colorectal cancer (CRC) cells through CEA-driven RR production.
Methods:
CEA enzyme-linked immunosorbent assay was performed on LS174T and HCT-8 human CRC cells. The CEA enhancer-promoter (CEA E-P) was functionally assessed by luciferase assay. CEA E-P was cloned upstream of UL39, the gene encoding the large subunit of RR. Cells were transfected with CEA E-P/UL39 and infected with G207 for cytotoxicity assays. LS174T, with or without CEA E-P/UL39, were implanted into athymic mouse flanks (n = 28) and treated with G207.
Results:
CEA levels were 7-fold higher in LS174T versus HCT-8 ( P <.00001). CEA E-P increased luciferase expression 7.5-fold in LS174T ( P <.01), with no increase in HCT-8. G207 cytotoxicity of'CEA E-P/UL39-transfected LS174T cells increased 69% by day 10 versus nontransfected cells ( P <.001), with no significant increase in HCT-8. Combining CEA E-P/UL39 with G207 in LS174T flank tumors resulted in a 65% decrease in tumor volume versus G207, phosphate-buffered saline, or'CEA E-P/UL39 alone ( P <.0001).
Conclusions:
CEA-driven RR production by CEA-secreting CRC cells significantly improves oncolytic viral cytotoxicity and specificity in vitro, and reduces tumor burden in vivo.
Insights
Genetically modifying colorectal cancer cells to produce more ribonucleotide reductase (RR) enhances oncolytic herpes virus (G207) effectiveness. This strategy improves viral cancer cell killing and reduces tumor size in vivo.
Area of Science:
- Oncolytic virology
- Cancer gene therapy
- Molecular oncology
Background:
- G207 is an oncolytic herpes virus requiring cellular ribonucleotide reductase (RR) for DNA synthesis.
- Enhancing RR production in cancer cells can improve oncolytic viral therapy efficacy.
Purpose of the Study:
- To enhance the oncolytic potency of G207 in colorectal cancer (CRC) cells.
- To achieve CEA-driven RR production for improved viral replication and cytotoxicity.
Main Methods:
- CEA enzyme-linked immunosorbent assay performed on LS174T and HCT-8 CRC cells.
- CEA enhancer-promoter (CEA E-P) cloned upstream of UL39 (RR gene) and transfected into cells.
- Cytotoxicity assays and in vivo tumor studies in athymic mice treated with G207.
Main Results:
- LS174T cells showed significantly higher CEA levels than HCT-8 cells.
- CEA E-P transfection increased RR production and G207 cytotoxicity by 69% in LS174T cells.
- Combined CEA E-P/UL39 and G207 treatment reduced LS174T tumor volume by 65% in vivo.
Conclusions:
- CEA-driven RR production enhances oncolytic viral cytotoxicity and specificity in CEA-producing CRC cells.
- This approach significantly reduces tumor burden in vivo, demonstrating therapeutic potential.
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