Despite the recent FDA approval of the oncolytic herpes simplex virus, ImlygicTM to treat melanoma, and the promising antitumor efficacy observed in many preclinical models using other similar viruses, strategies are still need to improve the anti-cancer effectiveness of herpes virotherapy. Our preliminarily results using a so-called ?directed evolution? strategy in a low-permissive cell culture support our overarching hypothesis that more effective virus mutants can be created via serial selection of mixed virus infections in poorly permissive cells. Combining sequencing analysis and CRISPR/Cas9 gene editing approaches, we developed our lead strain Mut-3?34.5, which is attenuated with RL1/?134.5 deletion. We found this novel virus induces a giant syncytia phenotype and contains five nonsynonymous alternations, including the A151T in Us8/gE, that potentially underlie the increased cancer cell killing effect of Mut-3?34.5.
The aims of this project are: (1) Determine the mechanism(s) underlying the increased potency of Mut-3?34.5 virus in oncolysis, (2) Delineate the role of the non-parental non-synonymous mutations in Mut-3?34.5 and (3) Define the safety profile and efficacy of attenuated Mut-3?34.5 virus in animal models. Our overarching goal is to further develop more potent yet safe viral vectors for future clinical use.

Public Health Relevance

We aim to develop more effective and safe herpes simplex viruses for cancer treatment. If we are successful, we will have developed new tools that can be studied in human clinical trials. If successful, these agents may reduce the burden of solid cancers by increasing cure rates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA223104-01A1
Application #
9647615
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Salomon, Rachelle
Project Start
2019-01-16
Project End
2020-12-31
Budget Start
2019-01-16
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205