The goal of this proposal is to develop improved oncolytic herpesviral vectors (oHSV) for the treatment of glioblastomas (GBM), a deadly cancer of the nervous system for which adequate therapy remains elusive Oncolytic viruses derive their anti-cancer activity from their ability to lyse cancer cells and spread within the tumor while sparing normal cells. Their selectivity for cancer cells is generally based on natural or engineered defects in the viral genome that inactivate key replication functions in normal cells but are complemented by the abnormal environment within cancer cells. HSV is an attractive vector for oncolytic therapy for tumors of the nervous system because of its natural neurotropism, high lytic activity, well-defined life cycle controlled by two essential genes, and capacity to deliver multiple exogenous anti-cancer protein products to enhance their efficacy. Clinical trials of current oncolytic HSV (oHSV) have demonstrated safety but limited efficacy, due in part to barriers examined by each of the projects of this program grant. Our study seeks to take advantage of new vector engineering technologies to achieve greater replication efficiency and oHSV spread within the tumor without compromising safety. We hypothesize that restricting oHSV infection to tumor cells by engineering steps referred to as retargeting, combined with measures to block virus replication in normal cells based on signature differences in microRNA expression profiles between normal and cancer cells, will provide a new generation of oHSVs that will prove both highly effective and safe.
In Aim 1, we will redirect oHSV infectivity to glioblastoma cells by viral envelope engineering and in collaboration with Project 2-3, test, the effect of HDAC inhibition and virus-mediated ectopic chondroitinase expression on oHSV distribution and spread.
In Aim 2, we will install genetic elements in the oHSV that will allow replication exclusively in glioblastoma cells as a function of the unique microRNA signatures of these cells.
In Aim 3, animal experiments will be performed to test the safety and efficacy of selected oHSVs that combine key features from the first two aims. With potential further improvements based on feedback from all other projects of this program, we expect that we will engineer a promising new generation of oHSV for evaluation in clinical trials.

Public Health Relevance

Clinical trials with conditionally-replicating herpesviruses (oHSV) for the treatment of glioblastoma multiforme have shown safety without consistent evidence of efficacy. This project, in close collaboration with Projects 2 and 3, seeks to address deficiencies in oHSV lytic activity and spread while ensuring safety by a combination of novel engineering steps that will eliminate the need for attenuating mutations in the viral genome, facilitate oHSV dissemination, and provide a possible solution for inefficient oHSV entry into glioblastoma cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163205-03
Application #
8796164
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$365,804
Indirect Cost
$115,482
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Dai, Hong-Sheng; Caligiuri, Michael A (2018) Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. Front Immunol 9:183
Chen, Luxi; Youssef, Youssef; Robinson, Cameron et al. (2018) CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway. Immunity 49:464-476.e4
Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572
Kim, Yangjin; Yoo, Ji Young; Lee, Tae Jin et al. (2018) Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy. Proc Natl Acad Sci U S A 115:4927-4932
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Scoville, Steven D; Nalin, Ansel P; Chen, Luxi et al. (2018) Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 132:1792-1804
Chan, Wing Keung; Kang, Siwen; Youssef, Youssef et al. (2018) A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol Res 6:776-787
Nakashima, Hiroshi; Alayo, Quazim A; Penaloza-MacMaster, Pablo et al. (2018) Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells. Sci Rep 8:208
Marzulli, M; Mazzacurati, L; Zhang, M et al. (2018) A Novel Oncolytic Herpes Simplex Virus Design based on the Common Overexpression of microRNA-21 in Tumors. J Gene Ther 3:
Russell, Luke; Swanner, Jessica; Jaime-Ramirez, Alena Cristina et al. (2018) PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nat Commun 9:5006

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