GBM-Targeted oHSV Armed with Matrix Metalloproteinase 9 Enhances Anti-tumor Activity and Animal Survival

Paola Sette; Nduka Amankulor; Aofei Li; Marco Marzulli; Daniela Leronni; Mingdi Zhang; William F Goins; Balveen Kaur; Chelsea Bolyard; Timothy P Cripe; Jianhua Yu; E Antonio Chiocca; Joseph C Glorioso; Paola Grandi

doi:10.1016/j.omto.2019.10.005

GBM-Targeted oHSV Armed with Matrix Metalloproteinase 9 Enhances Anti-tumor Activity and Animal Survival

Mol Ther Oncolytics. 2019 Oct 24:15:214-222. doi: 10.1016/j.omto.2019.10.005. eCollection 2019 Dec 20.

Authors

Paola Sette^{1

2}, Nduka Amankulor^{1

2}, Aofei Li³, Marco Marzulli³, Daniela Leronni^{1

2}, Mingdi Zhang³, William F Goins³, Balveen Kaur⁴, Chelsea Bolyard⁴, Timothy P Cripe^{5

6}, Jianhua Yu^{7

8

9}, E Antonio Chiocca^{10

11}, Joseph C Glorioso^{2

3}, Paola Grandi^{1

2}

Affiliations

¹ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
³ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Department of Neurological Surgery, Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA.
⁵ Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.
⁶ Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
⁷ Hematologic Malignancies & Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, USA.
⁸ Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
⁹ Division of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.
¹⁰ Department of Neurosurgery, Brigham and Women's/Faulkner Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medicine School, Boston, MA, USA.
¹¹ Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Abstract

The use of mutant strains of oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment of glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required for effective GBM therapy. Inadequate vector performance may derive from poor intratumoral vector replication and limited spread to uninfected cells. Vector replication may be impaired by mutagenesis strategies to achieve vector safety, and intratumoral virus spread may be hampered by vector entrapment in the tumor-specific extracellular matrix (ECM) that in GBM is composed primarily of type IV collagen. In this report, we armed our previously described epidermal growth factor receptor (EGFR)vIII-targeted, neuronal microRNA-sensitive oHSV with a matrix metalloproteinase (MMP9) to improve intratumoral vector distribution. We show that vector-expressed MMP9 enhanced therapeutic efficacy and long-term animal survival in a GBM xenograft model.

Keywords: Glioblastoma multiforme = GBM; OVs derived from herpes simplex virus = oHSV; Oncolytic vectors = OVs; extracellular matrix = ECM; matrix metalloproteinase 9 = MMP9.

Abstract

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