Glioblastoma, the most malignant primary brain tumor, has remained largely refractory to all forms of therapy, and is almost uniformly lethal with a median survival of approximately 15 months. The promise of immunotherapy in glioblastoma has yet to be realized, in part due to altered immune activities in the brain and the immunosuppressive microenvironment of glioblastoma. Recently isolated glioblastoma stem cells (GSCs) are thought to be important in the tumor's ability to evade therapy. In addition, the brain tumors they generate in mice retain many of the features of the patient tumors, so they provide a representative tumor model for testing new therapies, something that established cell lines do not. We, and others have developed oncolytic herpes simplex virus (oHSV) vectors that selectively replicate in and kill cancer cells, without harming the surrounding normal tissue or causing disease, and induce anti- tumor immune responses. The safety of oHSV has been demonstrated in clinical trials for glioblastoma; however, while clinical responses have been very promising, approval for use in the brain has not yet occurred, and improvements to this therapeutic strategy are warranted. The overall goal of our research program is to develop oHSV as therapeutic agents and elucidate combination strategies with them that will cure glioblastoma. Building on the progress in the last funding cycle, we propose to improve oHSV therapy by: (i) Creating new oHSV vectors that replicate efficiently in GSCs, are safe in the brain, and are optimally immunotherapeutic; (ii) Developing new oHSV combination strategies with inhibitors of DNA damage responses to target GSCs and take advantage of oHSV disruption of DNA repair; and (iii) Enhancing glioblastoma immunotherapy by combining DNA damage response inhibitors with oHSV and immune checkpoint inhibitors. Central to these studies is the use of representative tumor models; primary and recurrent patient-derived GSCs in immunodeficient mice and mouse syngeneic GSCs in immunocompetent mice. These studies should identify new synergistic drug / oHSV combinations that also promote immunovirotherapy. We anticipate that therapies demonstrated in the proposed studies will be translatable to the clinic for glioblastoma, and other brain tumors and solid tumors in the periphery.

Public Health Relevance

Glioblastoma, the most frequent malignant primary brain tumor, is invariably lethal within a short period of time irrespective of therapeutic modality. We are constructing new oncolytic herpes simplex viruses to target glioblastoma stem cells and treat glioblastoma, and will take advantage of the virus's ability to target DNA damage responses to develop new combinations with molecular targeted therapies. These studies should enhance our understanding of glioblastoma stem cells and provide the rationale for translating new combination strategies to the clinic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Welch, Anthony R
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Massachusetts General Hospital
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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
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
Esaki, Shinichi; Nigim, Fares; Moon, Esther et al. (2017) Blockade of transforming growth factor-? signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models. Int J Cancer 141:2348-2358
Ning, Jianfang; Wakimoto, Hiroaki; Peters, Cole et al. (2017) Rad51 Degradation: Role in Oncolytic Virus-Poly(ADP-Ribose) Polymerase Inhibitor Combination Therapy in Glioblastoma. J Natl Cancer Inst 109:1-13
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
Antoszczyk, Slawomir; Rabkin, Samuel D (2016) Prospect and progress of oncolytic viruses for treating peripheral nerve sheath tumors. Expert Opin Orphan Drugs 4:129-138
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
Saha, Dipongkor; Wakimoto, Hiroaki; Rabkin, Samuel D (2016) Oncolytic herpes simplex virus interactions with the host immune system. Curr Opin Virol 21:26-34
Saha, Dipongkor; Ahmed, Seemin S; Rabkin, Samuel D (2015) EXPLORING THE ANTITUMOR EFFECT OF VIRUS IN MALIGNANT GLIOMA. Drugs Future 40:739-749

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