HSV1716 Prevents Myeloma Cell Regrowth When Combined with Bortezomib In Vitro and Significantly Reduces Systemic Tumor Growth in Mouse Models

Simon Tazzyman; Georgia R Stewart; James Yeomans; Adam Linford; Darren Lath; Joe Conner; Munitta Muthana; Andrew D Chantry; Michelle A Lawson

doi:10.3390/v15030603

HSV1716 Prevents Myeloma Cell Regrowth When Combined with Bortezomib In Vitro and Significantly Reduces Systemic Tumor Growth in Mouse Models

Viruses. 2023 Feb 22;15(3):603. doi: 10.3390/v15030603.

Authors

Simon Tazzyman^{1

2

3}, Georgia R Stewart^{1

2

3}, James Yeomans^{1

2

3}, Adam Linford^{1

2

3}, Darren Lath^{1

2

3}, Joe Conner⁴, Munitta Muthana³, Andrew D Chantry^{1

2

3}, Michelle A Lawson^{1

2

3}

Affiliations

¹ Sheffield Myeloma Research Team, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
² Mellanby Centre for Musculoskeletal Research, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
³ Department of Oncology and Metabolism, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
⁴ Sorrento Therapeutics, 4955 Directors Place, San Diego, CA 92121, USA.

Abstract

Multiple myeloma remains largely incurable due to refractory disease; therefore, novel treatment strategies that are safe and well-tolerated are required. Here, we studied the modified herpes simplex virus HSV1716 (SEPREHVIR^®), which only replicates in transformed cells. Myeloma cell lines and primary patient cells were infected with HSV1716 and assessed for cell death using propidium iodide (PI) and Annexin-V staining and markers of apoptosis and autophagy by qPCR. Myeloma cell death was associated with dual PI and Annexin-V positivity and increased expression of apoptotic genes, including CASP1, CASP8, CASP9, BAX, BID, and FASL. The combination of HSV1716 and bortezomib treatments prevented myeloma cell regrowth for up to 25 days compared to only transient cell growth suppression with bortezomib treatment. The viral efficacy was tested in a xenograft (JJN-3 cells in NSG mice) and syngeneic (murine 5TGM1 cells in C57BL/KaLwRijHsd mice) systemic models of myeloma. After 6 or 7 days, the post-tumor implantation mice were treated intravenously with the vehicle or HSV1716 (1 × 10⁷ plaque forming units/1 or 2 times per week). Both murine models treated with HSV1716 had significantly lower tumor burden rates compared to the controls. In conclusion, HSV1716 has potent anti-myeloma effects and may represent a novel therapy for multiple myeloma.

Keywords: HSV1716; apoptosis; herpes simplex virus; multiple myeloma; oncolytic virus; systemic murine models.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Annexins
Apoptosis
Bortezomib / pharmacology
Bortezomib / therapeutic use
Cell Line, Tumor
Humans
Mice
Mice, Inbred C57BL
Multiple Myeloma* / drug therapy
Simplexvirus / genetics

Substances

Bortezomib
Annexins

Grants and funding

This research was funded by the University of Sheffield (Yorkshire Cancer Research Endowment Release—Pump Priming New Clinical Academic Chairs) and the University of Sheffield Open Access Fund.