The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) Vaccine Strain
VC2 Constitutively Expressing GM-CSF Causes Increased Intratumoral T
Cell Infiltration and Inhibition of Tumor Metastasis in the 4T1/Balb/c
Mouse Model of Stage Four Breast Cancer
- Rafiq Nabi,
- Vladimir Chouljenko,
- Farhana Musarrat,
- Megan Davis E,
- Harikrishnan Mohan,
- Reza Ghavimi,
- Brent Stanfield,
- Ojasvi Dutta,
- Gus Kousoulas
Gus Kousoulas
Louisiana State University
Corresponding Author:vtgusk@lsu.edu
Author ProfileAbstract
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Oncolytic virotherapy (OVT) aims to disrupt the tumor microenvironment
and provide a unique therapeutic approach against solid tumors. Herpes
Simplex Virus Type-1 (HSV-1) has shown strong promise for treating
various solid tumors and has been approved to treat melanoma and glioma
in human patients. Previously, we reported the generation of an
engineered HSV-1 vaccine strain VC2, which has shown exceptional promise
as an oncolytic and immunotherapeutic virus. In the present work, we
engineered VC2 to constitutively express the murine
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) gene inserted
in place of HSV-1 Glycoprotein C (gC). We tested the efficacy of
VC2-GMCSF for its ability to generate anti-tumor response in the 4T1
stage four metastatic breast cancer mouse model. GM-CSF expression
enhanced VC2 viral replication and infectious virus production. Tumors
formed after 7 days of engraftment in the mammary fat-pad of Balb/CJ
mice were treated by injecting ~10 6
plaque forming units (PFU) once. Intra-tumor treatment did not
appreciably reduce average primary tumor sizes. However, metastatic foci
were significantly reduced in mice lungs treated with VC2-GMCSF compared
to VC2 or mock treatment. VC2-GMCSF intratumoral treatment induced a
stronger intratumor T cell infiltration but not an increased cytotoxic
activity. A significant T cell infiltration was observed in the
metastatic areas in VC2-GMCSF treated animals, which was associated with
reduced pro-tumor marker PDL1 and VEGF gene expression. These results
show that constitutive expression of GM-CSF enhanced the overall
efficacy of VC2 for oncolytic virotherapy. VC2-GMCSF holds promise as an
oncolytic and immunotherapeutic virotherapy for breast and other
cancers.17 Sep 2024Submitted to Journal of Medical Virology 18 Sep 2024Submission Checks Completed
18 Sep 2024Assigned to Editor
18 Sep 2024Review(s) Completed, Editorial Evaluation Pending
19 Sep 2024Reviewer(s) Assigned
09 Oct 2024Editorial Decision: Revise Major