Details of a Researcher - Toda, Masahiro

Papers - Toda, Masahiro

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Identification of HLA-A2- And A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy

Ueda Ryo, Ohkusu-Tsukada Kozo, Fusaki Noemi, Soeda Akio, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 126 ( 4 ) 919 - 929 2010.02

ISSN 0020-7136

Malignant gliomas are the most aggressive human primary brain tumors and are currently incurable. Immunotherapies have the potential to target glioma and glioma stem cells (GSCs) that are resistant to conventional therapies. We previously identified SOX6 as a human glioma antigen and demonstrated that vaccination with SOX6 DNA induced cytotoxic T lymphocytes (CTLs) specific for glioma, thereby exerting therapeutic antitumor responses in glioma-bearing mice. In this study, we attempted to identify SOX6-derived peptides as specific targets for effective and safe T-cell-mediated immunotherapy targeting SOX6-positive glioma and GSCs. In vitro stimulation with human leukocyte antigen (HLA)-A*2402 (A24)-restricted peptides, RFENLGPQL (SOX6₅₀₄) and PYYEEQARL (SOX6₆₂₈) or the HLA-A*0201 (A2)-restricted peptide, ALFGDQDTV (SOX6₄₄₇) was capable of inducing SOX6 peptide-specific CTLs in peripheral blood mononuclear cells derived from healthy donors and glioma patients. These CTLs were able to lyse a majority of glioma cell lines and a GSC line derived from human glioblastoma in an HLA Class I-restricted and an antigen-dependent manner. Furthermore, peptide vaccines of SOX6₆₂₈, which was conserved in the murine SOX6 protein and expected to bind to major histocompatibility complex (MHC) H-2^d, induced CTLs specific for SOX6₆₂₈ in H-2^d mice. Normal autologous cells from mice, in which SOX6-specific immune responses were generated, were not destroyed. These results suggest that these SOX6 peptides are potnetially immunogenic in HLA-A24 or -A2 positive glioma patients and should be considered as a promising strategy for safe and effective T-cell-based immunotherapy of patients with gliomas. © 2009 UICC.

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Immunotherapy targeted at brain cancer stem cells

Toda Masahiro

Open Cancer Immunology Journal 3 48 - 50 2010

Progress in stem cell research has been associated with the discovery of the presence of cancer stem cells in a variety of malignant tumors, and because these cells are resistant to anticancer agents and radiotherapy, analysis of their properties has been rapidly pursued as an important target for the treatment of cancers, including malignant brain tumors. Brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods. Analyzing the properties of BCSCs is extremely important to developing treatment methods that target BCSCs. Although no treatment method targeting BCSCs has yet been established, several methods have been proposed based on their cell-biological characteristics. This article describes therapeutic strategies that target drug-resistance molecules and stem-cell-associated molecules as well as immunotherapy targeted at BCSCs. © Masahiro Toda; Licensee Bentham Open.

Transplantation of dendritic cells promotes functional recovery from spinal cord injury in common marmoset

Yaguchi Masae, Tabuse Masanao, Ohta Shigeki, Ohkusu-Tsukada Kozo, Takeuchi Tamaki, Yamane Junichi, Katoh Hiroyuki, Nakamura Masaya, Matsuzaki Yumi, Yamada Masayuki, Itoh Toshio, Nomura Tatsuji, Toyama Yoshiaki, Okano Hideyuki, Toda Masahiro

Neuroscience Research 65 ( 4 ) 384 - 392 2009.12

ISSN 0168-0102

We previously reported that implantation of dendritic cells (DCs) into the injured site activates neural stem/progenitor cells (NSPCs) and promotes functional recovery after spinal cord injury (SCI) in mice. Working toward clinical application of DC therapy for SCI, we analyzed whether DCs promote functional recovery after SCI in a non-human primate, the common marmoset (CM). CMs are usually born as dizygotic twins. They are thus natural bone marrow and peripheral blood chimeras due to sharing of the placental circulation between dizygotic twins, leading to functional immune tolerance. In this study, to identify adequate CM donor-and-host pairs, mixed leukocyte reaction (MLR) assays were performed. Then, CM-DCs were generated from the bone marrow of the twin selected to be donor and transplanted into the injured site of the spinal cord of the other twin selected to be host, 7 days after injury. Histological analyses revealed fewer areas of demyelination around the injured site in DC-treated CMs than in controls. Immunohistochemical analysis showed that more motor neurons and corticospinal tracts were preserved after SCI in DC-treated CMs. Motor functions were evaluated using three different behavior tests and earlier functional recovery was observed in DC-treated CMs. These results suggest DC therapy to possibly be beneficial in primates with SCI and that this treatment has potential for clinical application. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Therapeutic strategies targeting brain tumor stem cells

Toda Masahiro

Brain and Nerve 61 ( 7 ) 799 - 803 2009.07

ISSN 1881-6096

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Activation of dendritic-like cells and neural stem/progenitor cells in injured spinal cord by GM-CSF

Hayashi Kaori, Ohta Shigeki, Kawakami Yutaka, Toda Masahiro

Neuroscience Research 64 ( 1 ) 96 - 103 2009.05

ISSN 0168-0102

Previously, we demonstrated that implanted dendritic cells (DCs) in the injured spinal cord of adult mice exert a neurotrophic effect, resulting in the activation of endogenous neural stem/progenitor cells (NSPCs) and neurogenesis. Granulocyte-macrophage colony stimulating factor (GM-CSF), which is an essential cytokine for the generation of DCs from haematopoietic progenitor cells, has been shown to be beneficial for the treatment of spinal cord injury (SCI). In the present study, to evaluate the mechanisms underlying this therapeutic efficacy of GM-CSF, we investigated the effects of GM-CSF on the DC-like cells and NSPCs in the injured spinal cord. When GM-CSF was injected into the injured spinal cords of mice, the numbers of DC-like cells and activated microglia/macrophages around the lesion site increased, accompanied by an increase in BDNF expression. A significant increase in endogenous NSPCs was observed around the lesion site in the GM-CSF-treated mice compared with that in the controls. A neurosphere forming assay revealed that GM-CSF also induced the proliferation of NSPCs in vitro. Moreover, injection of GM-CSF into the lesion immediately after the SCI resulted in early recovery of the locomotor function of the injured mice. In conclusion, GM-CSF activated DC-like cells and NSPCs in the injured spinal cord, which was probably involved in its beneficial effects in cases of spinal cord injury. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Intraoperative navigation and fluorescence imagings in malignant glioma surgery

Toda Masahiro

Keio Journal of Medicine 57 ( 3 ) 155 - 161 2008.09

ISSN 0022-9717

The current basic goals in glioma surgery are radical tumor resection without triggering the development of new neurological deficits. Although complete removal of malignant gliomas is extremely difficult because of the tumors' infiltrative characteristics, gross total resection of the tumor is known to be associated with improved outcome in the patients. To enable safe and radical resection of malignant gliomas, especially those adjacent to eloquent brain areas, rapid progress has been made in the development of operative support techniques; e.g., navigation systems to provide information about the anatomical and functional locations in the brain and a fluorescence imaging technique for differentiating brain tumors from normal brain tissue. These intraoperative imaging techniques in glioma surgery have improved the functional outcomes of glioma patients.

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Functional recovery after spinal cord injury in mice through activation of microglia and dendritic cells after IL-12 administration

Yaguchi Masae, Ohta Shigeki, Toyama Yoshiaki, Kawakami Yutaka, Toda Masahiro

Journal of Neuroscience Research 86 ( 9 ) 1972 - 1980 2008.07

ISSN 0360-4012

We have previously reported that the transplantation of dendritic cells (DCs) brings about functional recovery after spinal cord injury in mice through the activation of endogenous microglia/macrophages and neural stem/progenitor cells. In this study, the effect of interleukin-12 (IL-12), which is secreted from DCs, was evaluated for the treatment of spinal cord injury in mice. Administration of IL-12 into the injured site significantly increased the number of activated microglia/macrophages and DCs as well as the expression of brain-derived neurotrophic factor surrounding the lesion site. Immunohistochemical analyses showed that de novo neurogenesis and remyelination were induced by IL-12 treatment. Furthermore, an open field test using Basso-Beattie-Brenham scoring revealed a significant improvement of locomotor function in mice treated with IL-12. These results suggest that IL-12 administration into the injured spinal cord results in a functional recovery through the activation of microglia/macrophages and DCs. © 2008 Wiley-Liss, Inc.

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Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6

Ueda Ryo, Kinoshita Eiko, Ito Rena, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 122 ( 10 ) 2274 - 2279 2008.05

ISSN 0020-7136

We previously reported identifying SOX6 as a glioma antigen by serological screening using a testis cDNA library. Its preferential expression and frequent IgG responses in glioma patients indicate that SOX6 may be a useful target for immunotherapy. To examine whether cytotoxic T-lymphocyte (CTL) responses specific for SOX6 to destroy glioma can be generated in vivo, we treated glioma-bearing mice by vaccination with a plasmid DNA encoding murine full-length SOX6 protein. Following SOX6-DNA vaccination, CTLs specific for SOX6-expressing glioma cells were induced, while normal autologous-cells that had restrictedly expressed SOX6 during embryogenesis were not destroyed. Furthermore, DNA vaccination with SOX6 exerted protective and therapeutic antitumor responses in the glioma-bearing mice. This antitumor activity was abrogated by the depletion of CD4 positive T cells and/or CD8 positive T cells. These results suggest that the SOX6 protein has multiple CTL and helper epitopes to induce antitumor activity and the effectiveness of SOX6-DNA vaccine for the prevention and treatment of glioma. © 2008 Wiley-Liss, Inc.

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Isolation and characterization of dendritic cells from common marmosets for preclinical cell therapy studies

Ohta Shigeki, Ueda Yoko, Yaguchi Masae, Matsuzaki Yumi, Nakamura Masaya, Toyama Yoshiaki, Tanioka Yoshikuni, Tamaoki Norikazu, Nomura Tatsuji, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Immunology 123 ( 4 ) 566 - 574 2008.04

ISSN 0019-2805

Dendritic cells (DCs) have important functions as modulators of immune responses, and their ability to activate T cells is of great value in cancer immunotherapy. The isolation of DCs from the peripheral blood of rhesus and African green monkeys has been reported, but the immune system in the common marmoset remains poorly characterized, although it offers many potential advantages for preclinical studies. In the present study, we devised methods, based on techniques developed for mouse and human DC preparation, for isolating DCs from three major tissue sources in the common marmoset: bone marrow (BM), spleen and peripheral blood. Each set of separated cells was analysed using the cell surface DC-associated markers CD11c, CD80, CD83, CD86 and human leucocyte antigen (HLA)-DR, all of which are antibodies against human antigens, and the cells were further characterized both functionally and morphologically as antigen-presenting cells. BM proved to be an excellent cell source for the isolation of DCs intended for preclinical studies on cell therapy, for which large quantities of cells are required. In the BM-derived CD11c⁺ cell population, cells exhibiting the characteristic features of DCs were enriched, with the typical DC morphology and the abilities to undergo endocytosis, to secrete interleukin (IL)-12, and to stimulate Xenogenic T cells. Moreover, BM-derived DCs produced the neurotrophic factor NT-3, which is also found in murine splenic DCs. These results suggest that BM-derived DCs from the common marmoset may be useful for biological analysis and for preclinical studies on cell therapy for central nervous system diseases and cancer. © 2007 Blackwell Publishing Ltd.

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Identification of a neuron-specific human gene, KIAA1110, that is a guanine nucleotide exchange factor for ARF1

Hattori Yujiro, Ohta Shigeki, Hamada Kenji, Yamada-Okabe Hisafumi, Kanemura Yonehiro, Matsuzaki Yumi, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Biochemical and Biophysical Research Communications 364 ( 4 ) 737 - 742 2007.12

ISSN 0006-291X

To identify neuron-specific genes, we performed gene expression profiling, cDNA microarray and in silico ESTs (expressed sequence tags) analyses. We identified a human neuron-specific gene, KIAA1110 (homologue of rat synArfGEF (Po)), that is a member of the guanine nucleotide exchange factor (GEF) for the ADP-ribosylation factor (ARF). RT-PCR analysis showed that the KIAA1110 gene was expressed specifically in the brain among adult human tissues, whereas no apparent expression was observed in immature neural tissues/cells, such as fetal brain, glioma tissues/cells, and neural stem/precursor cells (NSPCs). The KIAA1110 protein was shown to be expressed in mature neurons but not in undifferentiated NSPCs. Immunohistochemical analysis also showed that KIAA1110 was expressed in neurons of the human adult cerebral cortex. Furthermore, the pull-down assay revealed that KIAA1110 has a GEF activity toward ARF1 that regulates transport along the secretion pathway. These results suggest that KIAA1110 is expressed specifically in mature neurons and may play an important role in the secretion pathway as a GEF for ARF1. © 2007 Elsevier Inc. All rights reserved.

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Preferential expression and frequent IgG responses of a tumor antigen, SOX5, in glioma patients

Ueda Ryo, Yoshida Kazunari, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 120 ( 8 ) 1704 - 1711 2007.04

ISSN 0020-7136

We previously reported to identify SOX5 as a glioma antigen by serological screening using a testis cDNA library. The present study was designed to analyze SOXS expression, its immunoreactivity, and the correlation between SOX5 IgG responses and clinical features in glioma patients to evaluate the possibility of its use as a diagnostic marker. Quantitative RT-PCR and Western blot analysis revealed that SOX5 was expressed in glioma tissues, but not in normal adult tissues, except in the testis. An immunohistochemical analysis showed that SOX5 was expressed in glioma cells, but only a few SOX5-positive cells were detected in non-neoplastic tissues from the cerebral cortex. IgG antibodies against SOX5 were detected in sera from 8 of the 27 glioma patients (27.6%), 0 of the 14 patients with other brain diseases (0%), 1 of the 54 other cancer patients (1.9%) and 1 of the 37 healthy individuals (2.7%). Patients with glioblastotna (GBM) who showed IgG responses against SOX5 exhibited significantly better survival periods than GBM patients without SOX5 antibodies. In summary, SOX5 is aberrantly expressed in glioma and can be recognized as a glioma antigen using IgGs from the sera of glioma patients. Furthermore, there is a statistically significant correlation between the presence of SOX5 IgGs and survival in GBM patients, suggesting that the glioma antigen SOX5 may be useful not only as a diagnostic marker, but also as a prognostic marker in glioma patients. © 2007 Wiley-Liss, Inc.

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Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation

Udagawa Masaru, Kudo-Saito Chie, Hasegawa Go, Yano Kazuhito, Yamamoto Aiko, Yaguchi Masae, Toda Masahiro, Azuma Ichiro, Iwai Takehisa, Kawakami Yutaka

Clinical Cancer Research 12 ( 24 ) 7465 - 7475 2006.12

ISSN 1078-0432

Purpose: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. Experimental Design: Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. Results: These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8⁺ T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4⁺CD25 ⁺FoxP3⁺ regulatory T cells. Conclusions: This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases. © 2006 American Association for Cancer Research.

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Intracarotid injection of granulocyte-macrophage colony-stimulating factor induces neuroprotection in a rat transient middle cerebral artery occlusion model

Nakagawa Toru, Suga Sadao, Kawase Takeshi, Toda Masahiro

Brain Research 1089 ( 1 ) 179 - 185 2006.05

ISSN 0006-8993

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to promote collateral flow in patients with coronary artery disease and also to induce arteriogenesis in a rat hypoperfusion brain model. Activated macrophages have been shown to induce vascular proliferation and play an important role in ischemic stroke. In this study, we examined the therapeutic effect of GM-CSF on the ischemic brain by activating microglia/macrophages. Rats were subjected to 1-h intraluminal middle cerebral artery occlusion (MCAO) and received an intracarotid injection of GM-CSF (5 ng) or saline immediately after reperfusion. Infarct volume, neurological function and histological findings were assessed 48 h later. An intracarotid injection of GM-CSF reduced the infarct volume and improved neurological function at 48 h after reperfusion. Histological analysis revealed that the number of activated microglia/macrophages to be increased and the number of apoptotic cells to be decreased in the area of the penumbra. These results suggest that intracarotid injection of GM-CSF may have a therapeutic effect on brain ischemia via activation of microglia/macrophages. © 2006 Elsevier B.V. All rights reserved.

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Identification of a glioma antigen, GARC-1, using cytotoxic T lymphocytes induced by HSV cancer vaccine

Iizuka Yukihiko, Kojima Hidefumi, Kobata Tetsuji, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 118 ( 4 ) 942 - 949 2006.02

ISSN 0020-7136

Despite several ongoing clinical trials of immunotherapies against glioma, few glioma-specifk antigens recognized by cytotoxic T lymphocytes (CTLs) have been identified. We recently demonstrated that intratumoral inoculation with herpes simplex virus (HSV) as a cancer vaccine activates tumor-specific CTLs. To identify glioma antigens recognized by CTLs, we used the HSV cancer vaccine to vaccinate mice harboring a syngeneic mouse glioma cell line, GL261. From the splenocytes of the immunized mice, we generated an H-2D^b-restricted CTL line, GCL-1, that was specific for GL261. Then, a cDNA expression library generated from GL261 was screened with GCL-1, and a new gene encoding glioma antigen, GARC-1, was isolated. Sequence analysis revealed that the GARC-1 gene isolated from GL261 had a point mutation causing an amino acid change (Asp to Asn at position 81). T-cell epitope analysis revealed that the mutated peptide GARC-1_77-85 (AALLNKLYA) but not the wild-type peptide (AALLDKLYA), was recognized by GCL-1. These results suggest that HSV cancer vaccination may be a useful method for inducing tumor-specific CTLs and identifying tumor antigens. Furthermore, this GL261/GARC-1 murine glioma model may be useful for the development of immunotherapy for brain tumors. © 2005 Wiley-Liss, Inc.

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Identification of glioma-specific RFX4-E and -F isoforms and humoral immune response in patients

Matsushita Hirokazu, Uenaka Akiko, Ono Toshiro, Hasegawa Kosei, Sato Shuichiro, Koizumi Fumihito, Nakagawa Kazuhiko, Toda Masahiro, Shingo Tetsuro, Ichikawa Tomotsugu, Noguchi Yuji, Tamiya Takashi, Furuta Tomohisa, Kawase Takeshi, Date Isao, Nakayama Eiichi

Cancer Science 96 ( 11 ) 801 - 809 2005.11

ISSN 1347-9032

For regulatory factor X4 (RFX4), two alternatively spliced variants, RFX4-A and -B, were reported in the testis. In this study, we identified transcript variants RFX4-C, -D, -E, and -F, and demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) that RFX4-A, -B and -C mRNAs were expressed only in the testis, and RFX4-D mRNA was expressed only in normal brain tissues. In tumors, RFX4-E and -F in addition to RFX4-D mRNA were expressed in gliomas by rapid amplification of cDNA ends and RT-PCR analyses. Expression of RFX4 mRNA was not observed in other tumors, such as lung, esophageal, stomach, colon or liver cancers. Quantitative real-time RT-PCR using common primer pairs detecting all of the variant transcripts showed high expression in normal testis, low expression in the brain (1% compared to the expression in testis), and overexpression in 17 of 61 gliomas (28%). Western blot analysis using DC28 monoclonal antibody (mAb) produced against recombinant RFX4-D C-terminus protein showed expression of RFX4-A and -C proteins, but not RFX4-B protein, in the testis, and expression of RFX4-D protein in the brain. Moreover, expression of RFX4-E and -F proteins, but not RFX4-D protein, was observed in gliomas. Immunohistochemistry analysis using DC28 mAb showed positive staining in the nuclei of spermatocytes in the testis and glioma cells. Antibody against RFX4 was detected in the sera of 3 of 58 (5%) glioma patients by enzyme-linked immunosorbent assay, suggesting the immunogenicity of RFX4-E and -F proteins in glioma patients. © Japanese Cancer Association.

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Gene therapy for brain tumors using herpes simplex virus vector

Toda Masahiro

Nippon rinsho. Japanese journal of clinical medicine 63 Suppl 9 510 - 514 2005

ISSN 0047-1852

Identification of an epigenetically silenced gene, RFX1, in human glioma cells using restriction landmark genomic scanning

Ohashi Yohei, Ueda Masakazu, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

Oncogene 23 ( 47 ) 7772 - 7779 2004.10

ISSN 0950-9232

To identify the CpG islands differentially methylated in human glioma, we performed restriction landmark genomic scanning with a CpG methylation-sensitive enzyme. We found 12 spots, the intensity of which was entirely lost or decreased in both the human glioma tissues examined as compared with that in matched normal lymphocytes, indicating aberrant methylation of these CpG islands in gliomas. The expression of RFX1, one of the genes associated with the methylated CpG islands, was frequently decreased in human glioma cell lines and tissues. We also demonstrated that the isolated CpG island located in the seventh intron of the RFX1 gene had enhancer activity and was hypermethylated in all of the glioma tissues and cell lines analysed, but not in normal brains or lymphocytes. Treatment of glioma cells with a demethylating agent, 5-azacytidine, resulted in the expression of RFX1, indicating that the silencing of the RFX1 gene may be attributable to its methylation. RFX1 has been implicated in transcriptional downregulation of the proto-oncogene c-myc. By expression of the RFX1 gene, the cellular proliferative activity of glioma cells was suppressed. Taken together, these results suggest that the RFX1 gene may be epigenetically silenced in human gliomas and involved in glioma tumorigenesis.

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Identification of human tumor antigens and its implications for diagnosis and treatment of cancer

Kawakami Yutaka, Fujita Tomonobu, Matsuzaki Yuriko, Sakurai Toshiharu, Tsukamoto Makoto, Toda Masahiro, Sumimoto Hidetoshi

Cancer Science 95 ( 10 ) 784 - 791 2004.10

ISSN 1347-9032

Human tumor antigens recognized by T cells have been identified by means of various molecular biological and immunological methods, including cDNA expression cloning with patients' T cells and antibodies, cDNA subtraction using RDA and PCR differential display, systematic gene analysis such as DNA sequencing, CGH, DNA chip/microarray and SAGE, in vitro T cell induction and immunization of HLA transgenic mice. The identification of human tumor antigens has led to a better understanding of the nature of tumor antigens, anti-tumor immune responses in patients before and after immunotherapy, and tumor escape mechanisms. The information obtained from these researches has enabled us to develop and improve immunotherapy by attempting to overcome the identified problems, including intrinsically low immunogenicity of tumor antigens and several escape mechanisms, such as regulatory T cell induction. The existence of immunogenic unique antigens derived from genetic alterations in tumor cells, and the varied immunogenicity of shared tumor antigens among patients due to differing expression in tumor cells and immunoreactivity of patients, indicates that individualized immunotherapy should ideally be performed. The identified antigens will also be useful for development of diagnostic methods and molecular targeting therapy for cancer.

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Implantation of Dendritic Cells in Injured Adult Spinal Cord Results in Activation of Endogenous Neural Stem/Progenitor Cells Leading to De Novo Neurogenesis and Functional Recovery

Mikami Yuji, Okano Hideyuki, Sakaguchi Masanori, Nakamura Masaya, Shimazaki Takuya, Okano Hirotaka James, Kawakami Yutaka, Toyama Yoshiaki, Toda Masahiro

Journal of Neuroscience Research 76 ( 4 ) 453 - 465 2004.05

ISSN 0360-4012

We report a treatment for spinal cord injury involving implantation of dendritic cells (DCs), which act as antigen-presenting cells in the immune system. The novel mechanisms underlying this treatment produce functional recovery. Among the immune cells tested, DCs showed the strongest activity inducing proliferation and survival of neural stem/progenitor cells (NSPCs) in vitro. Furthermore, in DC-implanted adult mice, endogenous NSPCs in the injured spinal cord were activated for mitotic de novo neurogenesis. These DCs produced neurotrophin-3 and activated endogenous microglia in the injured spinal cord. Behavioral analysis revealed the locomotor functions of DC-implanted mice to have recovered significantly as compared to those of control mice. Our results suggest that DC-implantation exerts trophic effects, including activation of endogenous NSPCs, leading to repair of the injured adult spinal cord. © 2004 Wiley-Liss, Inc.

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Augmentation of Antitumor Immune Responses by Multiple Intratumoral Inoculations of Replication-Conditional HSV and Interleukin-12

Iizuka Yukihiko, Suzuki Ayuko, Kawakami Yutaka, Toda Masahiro

Journal of Immunotherapy 27 ( 2 ) 92 - 98 2004.03

ISSN 1524-9557

Intratumoral inoculation with a herpes simplex virus (HSV) mutant, G207, as an in situ cancer vaccine has been shown to inhibit tumor growth by inducing tumor-specific immune responses. Here, as a step toward the clinical application of this therapeutic approach, we evaluated different protocols for enhancing the antitumor effect. First, in a bilaterally established tumor model with CT26 colon carcinoma, we demonstrated that multiple intratumoral inoculations with G207 induced a greater antitumor effect on both the inoculated and distant tumors than did 1 or 2 inoculations. Second, to boost this antitumor effect, we developed 2 strategies: multiple in situ cancer vaccines with G207 in combination with systemic administration of recombinant interleukin-12 (rIL-12) (G207/systemic rIL-12) or local administration of rIL-12 (G207/local rIL-12). The antitumor effects in both the inoculated and distant tumors by the combined treatments were significantly greater than by either G207 or rIL- 12 treatment alone. G207/systemic rIL-12 and G207/local rIL-12 mediated the complete regression of both the inoculated and distant tumors in 67% and 79% of the animals, respectively. These results indicate that multiple intratumoral inoculations of G207 and systemic or local rIL- 12 administration work synergistically to facilitate tumor regression and that this combination of treatments may have potential for treating cancer metastasis.

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