The treatment for malignant glioma (glioblastoma) remains a challenge. Several experimental paradigms continue to be utilized in clinical trials, such as oncolytic viruses (OV), engineered or naturally occurring virus strains that replicate selectively in tumors. Oncolytic herpes simplex virus type 1 (oHSV) clinical trials have revealed its safety in humans with malignant gliomas, but more work is required to increase its efficacy. The investigators of this program project thus hypothesize that oHSV replication and dispersal in glioblastoma is curtailed by multiple oHSV-based and host-based barriers and responses during the very initial phases of viral infection and replication {aim 1). Understanding the nature of these barriers and responses would allow us to exploit both pharmacologic and genetic modalities to circumvent oHSV-based and host-based barriers and responses and increase the efficacy of malignant glioma virotherapy (aim 2). To achieve these aims, project 1 (PI: J. Glorioso) plans to re-engineer oHSV to redirect it towards glioma cell surface receptors while increasing its safety using microRNA-based translational controls of oHSV genes;Project 2 (PI: E.A. Chiocca) will characterize a novel mechanism of antiviral action within tumor cells that is based on one of the histone deacetylases, HDAC6, how it interacts with Interferon and how it shuttles post-entry oHSV towards lysosomes for xenophagy rather than nucleus for active replication;Project 3 (PI: B. Kaur) will determine how the stroma of the tumor microenvironment impedes oHSV dispersal and will utilize chondroitinase to counteract this;Project 4 (PI: M.A. Caligiuri) will show how the rapid NK cell activation against virally infected nervous system tumors is deleterious to therapy and will characterize the cellular and molecular effectors of this response. These 5 projects will be served by the unique resources provided by Core A (Biostatistics/ Administration: Chiocca/Fernadez) that provides biostatistical justification for al projects, Core B (oHSV Production: Goins) that provides all projects with the same stock of purified oHSV and Core C (Glioma Biorepository: Nakano) that provides all projects with patient-derived glioma spheroids (GSs) that recapitulate the human tumor phenotypic/genetic features.

Public Health Relevance

oHSV-based clinical trials of malignant gliomas have been well tolerated by humans, but more work is required to enhance the efficacy of the treatment. This program project will characterize fundamental barriers and host responses that are deleterious to the efficacy of oHSV and will provide solutions that will increase oHSV therapeutic effectiveness, while maintaining its current record of safety.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Daschner, Phillip J
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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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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