We have proposed the development of genetically engineered viral vectors that can selectively and efficiently infect and kill brain tumor cells in situ without harming surrounding brain cells and without causing systemic disease and have focused on conditionally-replicating mutants of herpes simplex virus-1 (HSV-1) which we have genetically engineered to be attenuated for neurovirulence. We developed the vector, G207, a multimutated HSV-1 that conditionally replicates in glioblastoma, malignant meningioma, and other tumors but is non-neuropathogenic in HSV-sensitive mice and subhuman primates. Safety and efficacy studies have been done to allow G207 to be considered for human trial. We have also demonstrated that G207 can induce a specific cell-mediate immune response to tumor cell surface antigens and that this can be boosted with the introduction of cytokines such as IL-12 into a defective vector grown with G207 as a helper virus. We now plan studies to optimize this treatment. We will study factors with possible adverse effects on the clinical use of HSV for brain tumor therapy such as the effects of co- treatment with steroids and the consequences of prior exposure to HSV on the efficacy of HSV-tumor therapy. Tumor models in mice will be used to test. The effects of exposure to steroids or of prior exposure and sero- positivity to HSV. In order to improve the specificity of targeted tumor cell destruction, we also construct and test transcriptionally targeted HSV vectors for selective destruction of cells expressing nestin or midkine. In order to improve the treatment of cells at a distance from virus inoculation, we will also explore the use of HSV vectors expressing cytokines, immune co-stimulatory molecules such as B7-1 and/or a suicide gene, or a combination of these in order to modulate the host immune system to optimize brain tumor therapy with HSV. Through our first grant, we have developed the first HSV vector that can be safely used for brain tumor therapy. Through these studies we expect to create the next generation of HSV vector with improved efficacy and selectivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032677-05
Application #
2692714
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1994-05-01
Project End
2003-03-31
Budget Start
1998-07-15
Budget End
1999-03-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Georgetown University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Saha, Dipongkor; Wakimoto, Hiroaki; Peters, Cole W et al. (2018) Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models. Clin Cancer Res 24:3409-3422
Saha, Dipongkor; Martuza, Robert L; Rabkin, Samuel D (2018) Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma. Immunotherapy 10:779-786
Chongsathidkiet, Pakawat; Jackson, Christina; Koyama, Shohei et al. (2018) Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med 24:1459-1468
Saha, Dipongkor; Martuza, Robert L; Rabkin, Samuel D (2017) Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell 32:253-267.e5
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Nigim, Fares; Esaki, Shin-Ichi; Hood, Michael et al. (2016) A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus. Neuro Oncol 18:1278-87
Esaki, Shinichi; Rabkin, Samuel D; Martuza, Robert L et al. (2016) Transient fasting enhances replication of oncolytic herpes simplex virus in glioblastoma. Am J Cancer Res 6:300-11
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Lu, Lei; Saha, Dipongkor; Martuza, Robert L et al. (2015) Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol 121:91-100
Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P et al. (2015) Targeting Hypoxia-Inducible Factor 1? in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment. J Neuropathol Exp Neurol 74:710-22

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