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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
  • +6
  • Rafiq Nabi,
  • Vladimir Chouljenko,
  • Farhana Musarrat,
  • Megan Davis E,
  • Harikrishnan Mohan,
  • Reza Ghavimi,
  • Brent Stanfield,
  • Ojasvi Dutta,
  • Gus Kousoulas
Rafiq Nabi
Louisiana State University
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Vladimir Chouljenko
Louisiana State University
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Farhana Musarrat
Louisiana State University
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Megan Davis E
Louisiana State University
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Harikrishnan Mohan
Louisiana State University
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Reza Ghavimi
Louisiana State University
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Brent Stanfield
Louisiana State University
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Ojasvi Dutta
Louisiana State University
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Gus Kousoulas
Louisiana State University

Corresponding Author:[email protected]

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Abstract

not-yet-known not-yet-known not-yet-known unknown 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