Neurosurgery

Apr 1985-Dec 1985

Assistant in Neurosurgery, Nagoya University Hospital

Jan 1986-Jul 1987

Chief in Neurosurgery, Shizuoka-Kousei Hospital

Jul 1987-Jan 1989

Postgraduate scholarship, National Institute of Neurosurgery, Budapest, Hungary

Feb 1989

Trainee, Allgemeines Krankenhaus (AKH), Vienna, Austria

Mar 1989-Jul 1989

Registrar, Department of Neurosugery, Nagoya Daini Red Cross Hospital

July 1989- Oct 1997

Instructor in Neurosurgery, Nagoya University Hospital

Dec 1994-Feb 1995

Teaching staff of Japan International Cooperation, Center (JICA) in Sanjay Gandhi Postgraduate, Institute of Medical Sciences at Lucknow, India

Nov 1997-Dec 1997

Overseas research foundation by Japanese Ministry of Education, Department of neurosurgery, The hospital for sick children, Toronto University, Toronto, Ontario, Canada

Nov 1997- Mar 2000

Assistant Professor in Neurosurgery, Nagoya University Hospital

April 2000- May 2002

Associate Professor in Bio-Medicine, Nagoya University School of Medicine

June 2002- May 2008

Associate Professor in The Center for Genetic and Regenerative Medicine, Nagoya University Hospital

June 2008-present

Professor, Department of Neurosurgery, Nagoya University Graduate School of Medicine

Research and Development of Genetic and Cellular Therapies for Neoplastic Disorders in the Central Nervous System

Toshihiko Wakabayashi, MD, PhD is currently a professor and chairman in the Department of Neurosurgery, as well as a co-director of Center for Genetic and Regenerative Medicine (CGRM) at Nagoya University Graduate School of Medicine. Dr. Wakabayashi’s major research interests lie in translational research for malignant brain tumors. Dr. Wakabayashi runs three clinical trials; liposome-mediated interferon-beta gene therapy for malignant gliomas, dendritic cell therapy vaccinated with Interleukin13-Receptor (IL-13R) alpha 2 peptide in patients with malignant gliomas, and molecular-targeting chemotherapy using a combination of temozolomide and interferon-beta. As a co-director of CGRM, Dr. Wakabayashi plays an important role in the management of Bio-Material Producing Facility in Nagoya University Hospital, which allows for Human Gene Therapy Non-viral Vector Production, as well as Cell Processing under the managing system of the International Organization for Standardization (ISO) 9001:2000 and 13485:2003, as well as Good Manufacturing Practice (GMP). As a skillful neurosurgeon, Dr. Wakabayashi is also interested in the image-assisted surgical treatment, which is in collaboration with School of Engineering. He utilizes an intraoperative MR imaging (iMRI) operating unit at Nagoya University Hospital. The iMRI unit is connected to a network which enables us to share not only real time usual operative images and planning, but also advanced 3D imaging and dynamic fusion images.

Accomplishments

1) Human gene therapy clinical trial for malignant gliomas by means of cationic liposome-entrapped human interferon-beta gene
This project aims to evaluate the safety and pilot effectiveness of gene therapy using human interferon-beta for malignant gliomas by means of cationic liposome. Until now, five patients were treated with this method, and all patients could be treated safely.

2) Immuno-cell therapy using with dendritic cells enhanced by HLA-A2 and -A24 restricted IL13R-alpha 2 peptide for malignant gliomas
This project aims to clarify the efficacy and safety of immunotherapy using dendritic cells enhanced by HLA-A2 and/or HLA-A24 restricted IL13R-alpha 2 peptide ex vivo. We have found the safety and a part of efficacy for recurrent malignant glioma patients treated. The Phase I clinical trial has been currently on going.

3) A Multicenter Clinical Trial of Interferon-beta and Temozolomide Combination Therapy for Newly Diagnosed Glioblastomas
This is a 2-arm phase II trial of interferon-beta (IFN-beta) and temozolomide (TMZ) combination therapy versus TMZ plus radiation therapy to compare the efficacy of each in the treatment of newly diagnosed glioblastomas (GBMs). Our final goal is to obtain evidence showing that IFN-beta enhances the chemosensitivity to TMZ and to confirm that this combination therapy is a global standard for the treatment of malignant gliomas. In 2007, Dr. Wakabayashi conducted a clinical study (INTEGRA study) to obtain evidence that IFN-beta enhances the chemosensitivity to TMZ and to confirm that this combination therapy is a global standard for the treatment of malignant gliomas. Eight medical institutions all over Japan participated in this study. Most of the patients are currently being followed up, and the preliminary results reveal that this combination therapy causes minimal toxicity. The most frequent toxic effect is the inhibition of hematopoiesis (leukopenia and neutropenia) that, in most cases, recovered within a month after the cessation of drug administration. Based on this feasibility study, Dr. Wakabayashi became a principal investigator to run a multicenter randomized clinical trial involving 25 neurosurgical institutions that belong to the Japan Clinical Oncology Group (JCOG).

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1. Wakabayashi T et al. p16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas. Neurosurgery. 64:455-61 (2009)
2. Ito M et al. Type I Interferon Inhibits Astrocytic Gliosis and Promotes Functional Recovery after Spinal Cord Injury by Deactivation of the MEK/ERK Pathway. J Neurotrauma. 26:41-53 (2009)
3. Oi S et al. Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2'-deoxycytidine in glioma cells. J Neurooncol. 92:15-22 (2009)
4. Wakabayashi T et al. A multicenter phase I trial of interferon-beta and temozolomide combination therapy for high-grade gliomas (INTEGRA Study). Jpn J Clin Oncol. 38:715-8 (2008)
5. Wakabayashi T et al. A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy. J Gene Med 10:329-339 (2008)
6. Natsume A et al. The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. Int J Cancer 122:2542-2553 (2008)
7. Shimato S et al. Identification of a human leukocyte antigen-A24-restricted T-cell epitope derived from interleukin-13 receptor alpha2 chain, a glioma-associated antigen. J Neurosurg 109:117-122 (2008)
8. Ishii D et al. Efficacy of temozolomide is correlated with 1p loss and methylation of the deoxyribonucleic acid repair gene MGMT in malignant gliomas. Neurologia medico-chirurgica 47:341-349 (2007)
9. Ishii J et al. The free-radical scavenger edaravone restores the differentiation of human neural precursor cells after radiation-induced oxidative stress. Neurosci lett. 423:225-230 (2007)
10. Shimato S et al. Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma. Gene Ther 14:1132-1142 (2007)
11. Takeuchi H et al. Intravenously transplanted human neural stem cells migrate to the injured spinal cord in adult mice in an SDF-1- and HGF-dependent manner. Neurosci lett 426:69-74 (2007)
12. Tsuno T et al. Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances anti-tumor effect of temozolomide in human glioma cells. J Neuro-oncol 2007:83(3):249-258.
13. Natsume A et al. IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Cancer Res. 65:7573-9 (2005)
14. Shimato S, et al. EGFR mutation in patients with brain metastases from lung cancer: correlation with the efficacy of gefitinib. Neuro-Oncol., 8, 137-44 (2006)
15. Yoshida J et al. Human gene therapy for malignant gliomas (Glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Human Gene Ther 15: 77-86 (2004)
16. Hatano N et al. Efficacy of post operative adjuvant therapy with human interferon beta, MCNU and radiation (IMR) for malignant glioma: comparison among three protocols. Acta Neurochir (Wien) 142: 633-639, (2000)
17. Okada H et al. Suppression of CD44 expression decreases migration and invasion of human glioma cells. Int J Cancer. 10:255-60 (1996)
18. Okada H et al. Anti-(glioma surface antigen) monoclonal antibody G-22 recognizes overexpressed CD44 in glioma cells. Cancer Immunol Immunother. 39:313-7 (1994)
19. Wakabayashi T et al. Characterization of neuroectodermal antigen by a monoclonal antibody and its application in CSF diagnosis of human glioma. J Neurosurg. 68:449-55 (1988)

2001 Outstanding paper award of 2001 Journal of chemical engineering of Japan
2007 Research Award of Japan Society of Gene Therapy
2008 Best Simulation Awards of Japan Virtual Reality Medical Society