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Published on: November 24, 2014
Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen
Hideki Kasuya1, Timothy M Pawlik, John T Mullen
1Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of gamma(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2alpha phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD(50). Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.
Insights
This study engineered a Herpes simplex virus 1 (HSV-1) mutant to target cancer cells expressing DF3/MUC1. This engineered virus, DF3gamma34.5, shows preferential replication in tumor cells, enhancing viral oncolysis potential.
Area of Science:
- Oncolytic virology
- Molecular oncology
- Gene therapy
Background:
- Viral oncolysis utilizes replication-conditional viruses to destroy tumors.
- Preferential viral replication in neoplastic cells is crucial for effective cancer therapy.
- Herpes simplex virus 1 (HSV-1) gamma(1)34.5 gene product dephosphorylates eukaryotic initiation factor 2alpha, promoting viral replication.
Purpose of the Study:
- To engineer an HSV-1 mutant (DF3gamma34.5) that replicates preferentially in DF3/MUC1-positive cancer cells.
- To evaluate the efficacy and safety of DF3gamma34.5 for cancer treatment.
- To assess the potential of using the DF3/MUC1 promoter to control viral replication in vivo.
Main Methods:
- Utilized the DF3/MUC1 promoter/enhancer sequence to regulate HSV-1 gamma(1)34.5 expression.
- Infected DF3/MUC1-positive and negative cells with DF3gamma34.5 to assess viral replication and eIF2alpha phosphatase activity.
- Evaluated in vivo efficacy against carcinoma xenografts in nude mice and assessed toxicity (LD50).
- Examined DF3gamma34.5 replication in human liver tumor specimens after intravascular perfusion.
Main Results:
- DF3gamma34.5 demonstrated preferential replication and eIF2alpha phosphatase activity in DF3/MUC1-positive cells.
- The engineered virus showed restricted biodistribution in vivo and reduced toxicity.
- Preferential replication was observed in DF3/MUC1-positive liver tumors.
- DF3gamma34.5 effectively reduced carcinoma xenografts in mice.
Conclusions:
- Regulating HSV-1 gamma(1)34.5 expression via the DF3/MUC1 promoter enables targeted viral replication in cancer cells.
- This strategy offers a promising approach for developing safer and more effective oncolytic HSV-1 mutants.
- DF3gamma34.5 shows potential as a targeted therapy for MUC1-expressing cancers.
