Generation of an Oncolytic Herpes Simplex Viral Vector Completely Retargeted to the GDNF Receptor GFRα1 for Specific Infection of Breast Cancer Cells.

Bonnie L. Hall,Justus B. Cohen,Joseph C. Glorioso,Daniela Leronni,William F. Goins,Yoshitaka Miyagawa

doi:10.3390/ijms21228815

Abstract

Oncolytic herpes simplex viruses (oHSV) are under development for the treatment of a variety of human cancers, including breast cancer, a leading cause of cancer mortality among women worldwide. Here we report the design of a fully retargeted oHSV for preferential infection of breast cancer cells through virus recognition of GFRα1, the cellular receptor for glial cell-derived neurotrophic factor (GDNF). GFRα1 displays a limited expression profile in normal adult tissue, but is upregulated in a subset of breast cancers. We generated a recombinant HSV expressing a completely retargeted glycoprotein D (gD), the viral attachment/entry protein, that incorporates pre-pro-GDNF in place of the signal peptide and HVEM binding domain of gD and contains a deletion of amino acid 38 to eliminate nectin-1 binding. We show that GFRα1 is necessary and sufficient for infection by the purified recombinant virus. Moreover, this virus enters and spreads in GFRα1-positive breast cancer cells in vitro and caused tumor regression upon intratumoral injection in vivo. Given the heterogeneity observed between and within individual breast cancers at the molecular level, these results expand our ability to deliver oHSV to specific tumors and suggest opportunities to enhance drug or viral treatments aimed at other receptors.

Highlights

Developing novel therapeutic approaches for the treatment of breast cancer is essential; in 2018, over 600,000 women worldwide died of breast cancer and over 2 million new breast cancer cases were reported [1]
herpeess simplleexx virus (HSV)-derived oncolytic vectors have been tested in clinical trials for the treatment of solid tumors, including breast cancer [6]
The apparent safety of HSV as an oncolytic agent via direct intratumoral injection and the resultant tumor cell killing represent an incentive for further refinement of HSV as a platform for breast cancer oncolytic therapy

Summary

Introduction

Developing novel therapeutic approaches for the treatment of breast cancer is essential; in 2018, over 600,000 women worldwide died of breast cancer and over 2 million new breast cancer cases were reported [1]. Oncolytic viruses (OV) have been created from a variety of virus species and have been tested in human clinical trials for a broad array of solid tumors, including breast cancer [2,3,4,5,6]. The oncolytic HSV(oHSV) vector Imlygic received U.S Food and Drug Administration approval in 2015 for treatment of melanoma [7] and clinical trial data demonstrated that Imlygic in conjunction with anti-checkpoint antibodies was even more effective than either therapy alone [8]. An attractive alternative approach is vector retargeting, whereby virus infection is restricted to cells expressing tumor-associated cell surface receptors [15]. We and others have shown that retargeted viruses can effectively treat tumors in multiple mouse model systems [16,19,20]

Methods

Results

Conclusion