63 results on '"Koichi Hirabayashi"'
Search Results
2. Intraoperative Placement of an Absorbable Spacer Prior to Radiation Therapy for a Malignant Peripheral Nerve Sheath Tumor
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Yuki Endo, Taichi Fukuzawa, Masahiro Irie, Hideyuki Sasaki, Hironori Kudo, Ryo Ando, Ryuji Okubo, Saori Katayama, Masatoshi Hashimoto, Kosuke Sato, Masahito Tachibana, Hidekazu Aoki, Masayuki Araya, Koichi Hirabayashi, Shoji Saito, Hidekazu Masaki, Yozo Nakazawa, Yoji Sasahara, and Motoshi Wada
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absorbable spacer ,malignant peripheral nerve sheath tumor ,radiation therapy ,proton beam therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
A 7-year-6-month-old female was diagnosed with a pelvic malignant peripheral nerve sheath tumor and lymph node metastases. Tumorectomy was performed after four cycles of chemotherapy. A 33-mm cystic lesion was observed around the left iliac muscle after three cycles of postoperative chemotherapy, and proton beam therapy (PBT) was recommended. She was referred for absorbable spacer (AS) placement. The left ovarian appendage (OA) was resected due to the direct tumor infiltration. The right OA was fixed to the uterosacral ligament. The AS was fixed to the lateral pelvis. The PBT (70.3 Gy relative biological effectiveness) was performed successfully with the AS, and she also had the reproducing possibility due to prevention of severe irradiation damage of the right OA. AS eliminated the surgical removal of spacers and enabled us high-dose PBT for residual tumor without severe irradiation damage including infertility.
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- 2022
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3. Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration
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Hongxia Li, Emily B. Harrison, Huizhong Li, Koichi Hirabayashi, Jing Chen, Qi-Xiang Li, Jared Gunn, Jared Weiss, Barbara Savoldo, Joel S. Parker, Chad V. Pecot, Gianpietro Dotti, and Hongwei Du
- Subjects
Science - Abstract
Therapeutic options for non-small cell lung cancer patients with brain metastases are limited. Here the authors design B7-H3 targeting CAR-T cells engineered to express the chemokine receptor CCR2b, and show improved accumulation in the brain and enhanced anti-tumor activity in preclinical models of lung cancer brain metastases.
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- 2022
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4. Computationally Guided Design of Single-Chain Variable Fragment Improves Specificity of Chimeric Antigen Receptors
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Andrey Krokhotin, Hongwei Du, Koichi Hirabayashi, Konstantin Popov, Tomohiro Kurokawa, Xinhui Wan, Soldano Ferrone, Gianpietro Dotti, and Nikolay V. Dokholyan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Chimeric antigen receptor (CAR)-T cell-based immunotherapy of malignant disease relies on the specificity and association constant of single-chain variable fragments (scFvs). The latter are synthesized from parent antibodies by fusing their light (VL) and heavy (VH)-chain variable domains into a single chain using a flexible linker peptide. The fusion of VL and VH domains can distort their relative orientation, thereby compromising specificity and association constant of scFv, and reducing the lytic efficacy of CAR-T cells. Here, we circumvent the complications of domains’ fusion by designing scFv mutants that stabilize interaction between scFv and its target, thereby rescuing scFv efficacy. We employ an iterative approach, based on structural modeling and mutagenesis driven by computational protein design. To demonstrate the power of this approach, we use the scFv derived from an antibody specific to a human leukocyte antigen A2 (HLA-A2)-HER2-derived peptide complex. Whereas the parental antibody is highly specific to its target, the scFv showed reduced specificity. Using our approach, we design mutations into scFvs that restore specificity of the original antibody. Keywords: protein design, single-chain variable fragment, chimeric antigen receptor, CAR T, antibody, cancer, HER2, HLA-A2, MHC, immunotherapy
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- 2019
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5. Nonocclusive Mesenteric Ischemia after Chemotherapy in an Adolescent Patient with a History of Three Allogeneic Hematopoietic Stem Cell Transplantations for Acute Lymphoblastic Leukemia
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Koichi Hirabayashi, Mitsuho Takatsuki, Mitsuo Motobayashi, Takashi Kurata, Shoji Saito, Tomonari Shigemura, Yozo Nakazawa, Kazuo Sakashita, Satoshi Ishizone, Hiroyoshi Ota, and Kenichi Koike
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acute lymphoblastic leukemia ,adolescent ,allogeneic hematopoietic stem cell transplantation ,chemotherapy ,nonocclusive mesenteric ischemia ,Pediatrics ,RJ1-570 - Abstract
Nonocclusive mesenteric ischemia (NOMI) is induced by intestinal vasospasm without thromboembolic occlusion and is associated with high morbidity and mortality. The estimated overall incidence of autopsy-verified fatal NOMI is 2.0 cases/100,000 person-years; however, no pediatric or adolescent cases have yet been reported. An 18-year-old female was diagnosed with B-cell precursor acute lymphoblastic leukemia at the age of 10 years. Our patient received three allogeneic hematopoietic stem cell transplantations but experienced hematological relapse after each. She received combination therapy of prednisolone, L-asparaginase, vincristine, and bortezomib after the third relapse. On Day 16 after the initiation of chemotherapy, she developed NOMI; therefore, we performed a right-sided hemicolectomy on Day 27. Nonocclusive mesenteric ischemia should be considered during the differential diagnosis of intestinal complications after chemotherapy, even in pediatric and adolescent patients.
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- 2017
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6. Enzyme-Linked Immunosorbent Spot Assay for the Detection of Wilms’ Tumor 1-Specific T Cells Induced by Dendritic Cell Vaccination
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Yumiko Higuchi, Terutsugu Koya, Miki Yuzawa, Naoko Yamaoka, Yumiko Mizuno, Kiyoshi Yoshizawa, Koichi Hirabayashi, Takashi Kobayashi, Kenji Sano, and Shigetaka Shimodaira
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enzyme-linked immunosorbent spot assay ,tetramer analysis ,dendritic cells ,antigen-specific cytotoxic T cells ,Wilms’ tumor 1 ,Biology (General) ,QH301-705.5 - Abstract
Background: Despite recent advances in cancer immunotherapy and the development of various assays for T cell assessment, a lack of universal standards within immune monitoring remains. The objective of this study was to evaluate the enzyme-linked immunosorbent spot (ELISpot) assay in comparison with major histocompatibility complex-tetramer analysis in the context of dendritic cell (DC)-based cancer immunotherapy. Methods: The ELISpot assay was performed on peripheral blood mononuclear cells to assess reproducibility, daily precision, and linearity using HLA-A*24:02-restricted Cytomegalovirus peptide. Wilms’ tumor 1 (WT1) antigen-specific cytotoxic T cells were then evaluated by both the ELISpot assay and WT1 tetramer analysis in peripheral blood from 46 cancer patients who received DC vaccinations pulsed with human leukocyte antigen (HLA)-A*24:02-restricted modified WT1 peptides. Results: The ELISpot assay was proven to have reproducibility (coefficient of variation (CV) ranged from 7.4% to 16.3%), daily precision (CV ranged from 5.0% to 17.3%), and linearity (r = 0.96–0.98). WT1-specific immune responses were detected by the ELISpot assay in 34 out of 46 patients (73.9%) post-vaccination. A Spearman’s rank-correlation coefficient of 0.82 between the ELISpot assay and WT1 tetramer analysis was obtained. Conclusion: This is the first report of a comparison of an ELISpot assay and tetramer analysis in the context of dendritic cell (DC)-based cancer immunotherapy. The ELISpot assay has reproducibility, linearity, and excellent correlation with the WT1 tetramer analysis. These findings suggest that the validated ELISpot assay is useful to monitor the acquired immunity by DC vaccination targeting WT1.
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- 2015
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7. Dendritic Cell-Based Adjuvant Vaccination Targeting Wilms’ Tumor 1 in Patients with Advanced Colorectal Cancer
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Shigetaka Shimodaira, Kenji Sano, Koichi Hirabayashi, Terutsugu Koya, Yumiko Higuchi, Yumiko Mizuno, Naoko Yamaoka, Miki Yuzawa, Takashi Kobayashi, Kenichi Ito, and Tomonobu Koizumi
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dendritic cell vaccines ,colorectal cancer ,Wilms’ tumor 1 ,immunohistochemistry ,tetramer analysis ,enzyme-linked immunosorbent spot assay ,Medicine - Abstract
Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.
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- 2015
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8. In Vivo Administration of Recombinant Human Granulocyte Colony-Stimulating Factor Increases the Immune Effectiveness of Dendritic Cell-Based Cancer Vaccination
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Shigetaka Shimodaira, Ryu Yanagisawa, Terutsugu Koya, Koichi Hirabayashi, Yumiko Higuchi, Takuya Sakamoto, Misa Togi, Tomohisa Kato, Takashi Kobayashi, Tomonobu Koizumi, Shigeo Koido, and Haruo Sugiyama
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dendritic cell ,cancer vaccine ,vaccination ,acquired immunity ,granulocyte colony-stimulating factor ,tetramer analysis ,Medicine - Abstract
Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16−18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.
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- 2019
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9. Improvement of Pitting Corrosion Resistance of Type 316L Stainless Steel by Potentiostatic Removal of Surface MnS Inclusions
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Nobuyoshi Hara, Koichi Hirabayashi, Yu Sugawara, and Izumi Muto
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Materials of engineering and construction. Mechanics of materials ,TA401-492 - Abstract
The beneficial effect of the removal of MnS inclusions on the pitting of stainless steels has been demonstrated in two ways. (1) High-purity Type 316L stainless steel with no inclusions was used as a specimen in the measurement of anodic polarization curves in 0.5 M NaCl and (2) commercial Type 316L stainless steel with MnS and slag-related inclusions was first polarized at different potentials for 30 min in 1 M Na2SO4 of pH 3 and then anodic polarization measurements were taken in 0.5 M NaCl. Pitting did not occur in the passive or transpassive region of the high-purity steel. The polarization treatment dissolved MnS and some oxide inclusions (CaO and SiO2) on the surface of the commercial steel. An increase in pitting potential of the commercial steel was noted after treatment at potentials above 0.2 V. At the same time, the number of current spikes due to metastable pits decreased significantly. These results are more likely due to the beneficial effect of removing MnS inclusions from the steel surface rather than the modification effect of the chemical composition of passive films on the surface.
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- 2012
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10. Data from Cancer Immunotherapy with T Cells Carrying Bispecific Receptors That Mimic Antibodies
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Gianpietro Dotti, Rihe Liu, Barbara Savoldo, Hongxia Li, Koichi Hirabayashi, Keliang Gao, Chuang Sun, Jingjing Li, and Sarah Ahn
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Tumors are inherently heterogeneous in antigen expression, and escape from immune surveillance due to antigen loss remains one of the limitations of targeted immunotherapy. Despite the clinical use of adoptive therapy with chimeric antigen receptor (CAR)–redirected T cells in lymphoblastic leukemia, treatment failure due to epitope loss occurs. Targeting multiple tumor-associated antigens (TAAs) may thus improve the outcome of CAR-T cell therapies. CARs developed to simultaneously target multiple targets are limited by the large size of each single-chain variable fragment and compromised protein folding when several single chains are linearly assembled. Here, we describe single-domain antibody mimics that function within CAR parameters but form a very compact structure. We show that antibody mimics targeting EGFR and HER2 of the ErbB receptor tyrosine kinase family can be assembled into receptor molecules, which we call antibody mimic receptors (amR). These amR can redirect T cells to recognize two different epitopes of the same antigen or two different TAAs in vitro and in vivo.
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- 2023
11. Supplementary Data from Cancer Immunotherapy with T Cells Carrying Bispecific Receptors That Mimic Antibodies
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Gianpietro Dotti, Rihe Liu, Barbara Savoldo, Hongxia Li, Koichi Hirabayashi, Keliang Gao, Chuang Sun, Jingjing Li, and Sarah Ahn
- Abstract
Supplementary figures 1-6
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- 2023
12. Study on Electromagnetic Resonance Antennas in the Vicinity of Human Body
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Toshiya Hiramoto, Koichi Hirabayashi, and Keisuke Noguchi
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- 2022
13. Comment on: Assessment of kidney function using inulin‐based and estimated glomerular filtration rates before and after allogeneic hematopoietic stem cell transplantation in pediatric patients
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Daisuke Matsuoka, Koichi Hirabayashi, Tsubasa Murase, Shoji Saito, and Yozo Nakazawa
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Oncology ,Creatinine ,Pediatrics, Perinatology and Child Health ,Hematopoietic Stem Cell Transplantation ,Inulin ,Humans ,Hematology ,Child ,Kidney ,Glomerular Filtration Rate - Published
- 2022
14. Skin and soft tissue infections in adolescent chronic myeloid leukemia under dasatinib treatment
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Eriko Uchida, Shoji Saito, Daisuke Morita, Eri Okura, Koichi Hirabayashi, Miyuki Tanaka, Hideyuki Nakazawa, Akane Minagawa, and Yozo Nakazawa
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Adult ,Pyrimidines ,Oncology ,Adolescent ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Soft Tissue Infections ,Pediatrics, Perinatology and Child Health ,Dasatinib ,Imatinib Mesylate ,Humans ,Hematology ,Protein Kinase Inhibitors ,Retrospective Studies - Abstract
Although skin complications are common adverse events from tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML), no reports have focused on skin and soft tissue infections (SSTIs) associated with TKI use. We herein present five episodes of SSTIs in three CML patients under dasatinib treatment. All patients were adolescents and had been receiving dasatinib for more than 4 years. In contrast, none of 41 adult CML patients experienced SSTIs in a retrospective analysis. Our findings suggest that long-term dasatinib treatment in adolescent patients may be associated with the increased risk of SSTIs.
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- 2022
15. Computationally Guided Design of Single-Chain Variable Fragment Improves Specificity of Chimeric Antigen Receptors
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Xinhui Wan, Nikolay V. Dokholyan, Gianpietro Dotti, Konstantin I. Popov, Andrey Krokhotin, Koichi Hirabayashi, Soldano Ferrone, Hongwei Du, and Tomohiro Kurokawa
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0301 basic medicine ,Cancer Research ,CAR T ,Protein design ,Mutagenesis (molecular biology technique) ,chemical and pharmacologic phenomena ,Computational biology ,Human leukocyte antigen ,Major histocompatibility complex ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,antibody ,HER2 ,Single-chain variable fragment ,cancer ,Pharmacology (medical) ,single-chain variable fragment ,protein design ,biology ,chimeric antigen receptor ,Chemistry ,respiratory system ,HLA-A2 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Chimeric antigen receptor ,3. Good health ,030104 developmental biology ,Oncology ,Lytic cycle ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,immunotherapy ,Antibody ,MHC - Abstract
Chimeric antigen receptor (CAR)-T cell-based immunotherapy of malignant disease relies on the specificity and association constant of single-chain variable fragments (scFvs). The latter are synthesized from parent antibodies by fusing their light (VL) and heavy (VH)-chain variable domains into a single chain using a flexible linker peptide. The fusion of VL and VH domains can distort their relative orientation, thereby compromising specificity and association constant of scFv, and reducing the lytic efficacy of CAR-T cells. Here, we circumvent the complications of domains’ fusion by designing scFv mutants that stabilize interaction between scFv and its target, thereby rescuing scFv efficacy. We employ an iterative approach, based on structural modeling and mutagenesis driven by computational protein design. To demonstrate the power of this approach, we use the scFv derived from an antibody specific to a human leukocyte antigen A2 (HLA-A2)-HER2-derived peptide complex. Whereas the parental antibody is highly specific to its target, the scFv showed reduced specificity. Using our approach, we design mutations into scFvs that restore specificity of the original antibody. Keywords: protein design, single-chain variable fragment, chimeric antigen receptor, CAR T, antibody, cancer, HER2, HLA-A2, MHC, immunotherapy
- Published
- 2019
16. Dual Targeting CAR-T Cells with Optimal Costimulation and Metabolic Fitness enhance Antitumor Activity and Prevent Escape in Solid Tumors
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Koichi, Hirabayashi, Hongwei, Du, Yang, Xu, Peishun, Shou, Xin, Zhou, Giovanni, Fucá, Elisa, Landoni, Chuang, Sun, Yuhui, Chen, Barbara, Savoldo, and Gianpietro, Dotti
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Receptors, Chimeric Antigen ,CD28 Antigens ,Neoplasms ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Humans ,Xenograft Model Antitumor Assays - Abstract
Chimeric antigen receptor (CAR) T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing transacting CD28 and 4-1BB costimulation, while sharing the sane CD3ζ-chain cause rapid antitumor effects in
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- 2021
17. Impact of acute kidney injury on overall survival in children and young adults undergoing allogeneic hematopoietic stem cell transplantation
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Shoji Saito, Tsubasa Murase, Daisuke Matsuoka, Yozo Nakazawa, and Koichi Hirabayashi
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medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Disease ,urologic and male genital diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Young adult ,Child ,Retrospective Studies ,urogenital system ,business.industry ,Incidence (epidemiology) ,Incidence ,Acute kidney injury ,Hematopoietic Stem Cell Transplantation ,Hematology ,Acute Kidney Injury ,medicine.disease ,female genital diseases and pregnancy complications ,Confidence interval ,Survival Rate ,Oncology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Complication ,business ,030215 immunology - Abstract
Background Acute kidney injury (AKI) is a complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Increasing severity of AKI is associated with an increased risk of death. However, the impact of AKI in patients with malignant versus nonmalignant disease has not been reported. We investigated the incidence of AKI within the first 100 days after allo-HSCT and the impact of AKI on both 3-year overall survival (OS) and cumulative incidence of death after allo-HSCT in all patients and in patients with/without malignant primary diseases. Methods We performed a retrospective analysis of 107 consecutive pediatric and young adult patients who received their first allo-HSCT. AKI was classified into three grades according to the Acute Kidney Injury Network classification system. Results The cumulative incidences of AKI stages 1-3, 2-3, and 3, at day 100 after allo-HSCT were 34.6% (95% confidence interval [CI], 25.7%-43.6%), 17.8% (95% CI, 11.2%-25.6%), and 3.7% (95% CI, 1.2%-8.6%), respectively. OS was reduced for patients with AKI compared with patients without AKI (60.4% vs. 79.6%, p = .038). The cumulative incidence of death in the AKI group with nonmalignant disease was significantly higher than that in the no-AKI group (44.4% vs. 0%, p = .003). Conclusion AKI after allo-HSCT was not only a frequent event but also related to reduced OS. We recommend that all patients receiving allo-HSCT, especially patients with nonmalignant diseases, be closely monitored for AKI.
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- 2021
18. Cancer Immunotherapy with T Cells Carrying Bispecific Receptors That Mimic Antibodies
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Koichi Hirabayashi, Chuang Sun, Hongxia Li, Keliang Gao, Barbara Savoldo, Sarah Ahn, Jingjing Li, Rihe Liu, and Gianpietro Dotti
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Male ,0301 basic medicine ,Cancer Research ,Receptor, ErbB-2 ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Cell ,Immunotherapy, Adoptive ,Antibodies ,Article ,Epitope ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Antigen ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Receptor ,biology ,Chemistry ,In vitro ,Chimeric antigen receptor ,ErbB Receptors ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Antibody - Abstract
Tumors are inherently heterogeneous in antigen expression, and escape from immune surveillance due to antigen loss remains one of the limitations of targeted immunotherapy. Despite the clinical use of adoptive therapy with chimeric antigen receptor (CAR)–redirected T cells in lymphoblastic leukemia, treatment failure due to epitope loss occurs. Targeting multiple tumor-associated antigens (TAAs) may thus improve the outcome of CAR-T cell therapies. CARs developed to simultaneously target multiple targets are limited by the large size of each single-chain variable fragment and compromised protein folding when several single chains are linearly assembled. Here, we describe single-domain antibody mimics that function within CAR parameters but form a very compact structure. We show that antibody mimics targeting EGFR and HER2 of the ErbB receptor tyrosine kinase family can be assembled into receptor molecules, which we call antibody mimic receptors (amR). These amR can redirect T cells to recognize two different epitopes of the same antigen or two different TAAs in vitro and in vivo.
- Published
- 2019
19. Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors
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Koichi Hirabayashi, Yuhui Chen, Peishun Shou, Yang Xu, Chuang Sun, Xin Zhou, Giovanni Fucà, Barbara Savoldo, Elisa Landoni, Gianpietro Dotti, and Hongwei Du
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Cancer Research ,Cell signaling ,Effector ,medicine.medical_treatment ,CD28 ,Immunotherapy ,Biology ,Chimeric antigen receptor ,Oncology ,Tumor Escape ,Cancer immunotherapy ,Antigen ,Cancer research ,medicine - Abstract
Chimeric antigen receptor (CAR)-T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T-cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing trans-acting CD28 and 4-1BB co-stimulation, while sharing the same CD3ζ-chain cause rapid antitumor effects in in vivo stress conditions, protection from tumor re-challenge and prevention of tumor escape due to low antigen density. Molecular and signaling studies indicate that T cells engineered with the proposed CAR design demonstrate sustained phosphorylation of T-cell-receptor-associated signaling molecules and a molecular signature supporting CAR-T-cell proliferation and long-term survival. Furthermore, metabolic profiling of CAR-T cells displayed induction of glycolysis that sustains rapid effector T-cell function, but also preservation of oxidative functions, which are critical for T-cell long-term persistence. Dotti and colleagues present a CAR design featuring trans-acting CD28 and 4-1BB co-stimulation and shared CD3ζ-chain, which improved CAR-T cell metabolic and antitumor functions and avoided tumor escape through simultaneous targeting of two antigens.
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- 2021
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20. Assessment of kidney function using inulin‐based and estimated glomerular filtration rates before and after allogeneic hematopoietic stem cell transplantation in pediatric patients
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Tsubasa Murase, Yozo Nakazawa, Yoshihiko Hidaka, Koichi Hirabayashi, Daisuke Matsuoka, and Shoji Saito
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Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Urology ,Renal function ,Hematopoietic stem cell transplantation ,Kidney ,Kidney Function Tests ,urologic and male genital diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Prospective Studies ,Cystatin C ,Child ,Prospective cohort study ,Blood urea nitrogen ,Creatinine ,Inulin Clearance ,biology ,urogenital system ,business.industry ,Hematopoietic Stem Cell Transplantation ,Inulin ,Hematology ,Prognosis ,medicine.disease ,Oncology ,chemistry ,Child, Preschool ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,biology.protein ,Female ,business ,Biomarkers ,Follow-Up Studies ,Glomerular Filtration Rate ,030215 immunology ,Kidney disease - Abstract
Background Accurate evaluation of kidney function before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for both informed decision making and detection of chronic kidney disease. However, to the best of our knowledge, no report has evaluated the glomerular filtration rate (GFR) in pediatric patients who underwent HSCT using the gold standard GFR measurement, as well as inulin-based GFR (iGFR). Methods We assessed iGFR before and after allo-HSCT to evaluate the impact of allo-HSCT on GFR in a prospective cohort study of 17 pediatric patients. We also assessed the accuracy and bias of the values of estimated GFR (eGFR) calculated using serum creatinine (Cr), cystatin C (CysC), beta-2 microglobulin (β2 MG), 24-h creatinine clearance (24hCcr), and the full chronic kidney disease in children (CKiD) index that combines Cr, CysC, and blood urea nitrogen-based equations with iGFR as a reference to identify the most reliable equation for GFR. Results There was no significant difference between the values before and after allo-HSCT. CKiD CysC-, 24hCcr-, and full CKiD-based values showed good within 30% (P30) accuracy (80.6%, 79.3%, and 80.6%, respectively), but only 24hCcr and full CKiD had good mean bias (8.5% and 8.9%, respectively) and narrow 95% limits of agreement (-32.2 to 52.7 mL/min/1.73 m2 and -29.3 to 47.4 mL/min/1.73 m2 , respectively) compared with the corresponding iGFR. Conclusion There was no significant impact of allo-HSCT on GFR in our cohort. The most reliable equations for pediatric patients with allo-HSCT were eGFR-24hCcr and eGFR-full CKiD.
- Published
- 2020
21. Cancer Immunotherapy in Children
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Barbara Savoldo, Koichi Hirabayashi, and Gianpietro Dotti
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Oncology ,medicine.medical_specialty ,Cancer immunotherapy ,business.industry ,Internal medicine ,medicine.medical_treatment ,medicine ,business - Abstract
This chapter discusses the principle of cancer immunotherapy in children and adolescents, starting with the most common form of cellular immunotherapy: allogeneic haematopoietic stem-cell transplantation (HSCT). It then discusses specific immunotherapy strategies based on the administration of classic monoclonal antibodies (mAbs) targeting tumour-associated antigens, novel bispecific antibodies that simultaneously target tumour-associated antigens and activate CD3+ T lymphocytes, and mAbs that block key inhibitory molecules of the immune system (checkpoint blockade). Finally, the chapter describes specific cellular immunotherapy approaches, such as tumour vaccine and adoptive transfer of immune cells. Although only a few immunotherapies have so far been incorporated into the standard practice for paediatric cancers, their role is enjoying a new revival, after the promising results obtained in recent clinical trials.
- Published
- 2020
22. THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells
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Yang Xu, Peishun Shou, Barbara Savoldo, Ourania Tsahouridis, Kyogo Suzuki, Hongwei Du, Koichi Hirabayashi, Lishan Su, Sarah Ahn, Gianpietro Dotti, Yuhui Chen, Laura E. Herring, Guangming Li, and Chuang Sun
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,T-Lymphocytes ,Phosphatase ,Receptors, Antigen, T-Cell ,Priming (immunology) ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,03 medical and health sciences ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,0302 clinical medicine ,CD28 Antigens ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptors, Chimeric Antigen ,Kinase ,Chemistry ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,Intracellular Signaling Peptides and Proteins ,CD28 ,hemic and immune systems ,Chimeric antigen receptor ,Cell biology ,030104 developmental biology ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Phosphorylation ,Phosphatase complex ,Cytokines ,Intercellular Signaling Peptides and Proteins ,human activities - Abstract
Summary Chimeric antigen receptor (CAR) T cell costimulation mediated by CD28 and 4-1BB is essential for CAR-T cell-induced tumor regression. However, CD28 and 4-1BB differentially modulate kinetics, metabolism and persistence of CAR-T cells, and the mechanisms governing these differences are not fully understood. We found that LCK recruited into the synapse of CD28-encoding CAR by co-receptors causes antigen-independent CAR-CD3ζ phosphorylation and increased antigen-dependent T cell activation. In contrast, the synapse formed by 4-1BB-encoding CAR recruits the THEMIS-SHP1 phosphatase complex that attenuates CAR-CD3ζ phosphorylation. We further demonstrated that the CAR synapse can be engineered to recruit either LCK to enhance the kinetics of tumor killing of 4-1BB CAR-T cells or SHP1 to tune down cytokine release of CD28 CAR-T cells.
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- 2020
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23. Proton Beam Therapy for Adolescent Primary Central Nervous System Lymphoma With Residual Tumor After Intensive Chemotherapy: A Case Report
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Hidekazu Masaki, Kazutoshi Komori, Masayuki Araya, Miyuki Tanaka, Katsunori Tauchi, Takashi Kurata, Daisuke Morita, Koichi Hirabayashi, Yozo Nakazawa, Keiichiro Koiwai, and Shoji Saito
- Subjects
Male ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Salvage treatment ,Intensive chemotherapy ,030218 nuclear medicine & medical imaging ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Pediatric oncology ,Proton Therapy ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Brain magnetic resonance imaging ,Adverse effect ,business.industry ,Brain Neoplasms ,Lymphoma, Non-Hodgkin ,Radiotherapy Planning, Computer-Assisted ,Primary central nervous system lymphoma ,Brain ,Dose-Response Relationship, Radiation ,Chemoradiotherapy ,medicine.disease ,Magnetic Resonance Imaging ,Lymphoma ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Radiology ,medicine.symptom ,business - Abstract
Primary central nervous system lymphoma (PCNSL) is a very rare type of non-Hodgkin lymphoma. Although pediatric and adolescent PCNSL patients generally respond well to intensive chemotherapy, the salvage treatment for this condition remains uncertain for patients exhibiting a poor/suboptimal response to primary therapy. Proton beam therapy (PBT) is being increasingly employed especially for pediatric oncology cases. However, the safety and feasibility of PBT for PCNSL patients have not been addressed. We encountered an adolescent patient with PCNSL exhibiting 4 of 5 adverse prognostic factors at diagnosis and a residual tumor adjacent to the pituitary gland with gadolinium enhancement on brain magnetic resonance imaging after 7 courses of intensive chemotherapy. We selected local PBT at a dose of 30.6 Gy (relative biological effectiveness) as a salvage treatment for the residual tumor. After PBT, gadolinium enhancement of the residual lesion rapidly disappeared with no acute adverse effects. Moreover, during 30 months of follow-up, no neurological or endocrinological adverse effects have been observed despite the location of the tumor. The patient is now healthy and has shown no evidence of relapse. PBT deserves further investigation as a salvage treatment option for PCNSL patients exhibiting a suboptimal response to primary chemotherapy.
- Published
- 2019
24. Comparative analysis of graft-versus-host disease prophylaxis with tacrolimus in combination with methylprednisolone or methotrexate after umbilical cord blood transplantation
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Kazutoshi Komori, Eri Okura, Miyuki Tanaka, Shoji Saito, Yozo Nakazawa, Daisuke Morita, Ryu Yanagisawa, Tomonari Shigemura, Koichi Hirabayashi, Takashi Kurata, and Kazuo Sakashita
- Subjects
medicine.medical_specialty ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Gastroenterology ,Methylprednisolone ,Tacrolimus ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Neutrophil Engraftment ,Hematology ,Umbilical Cord Blood Transplantation ,business.industry ,medicine.disease ,Fetal Blood ,stomatognathic diseases ,surgical procedures, operative ,Graft-versus-host disease ,Methotrexate ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Post-transplant early immune disorders and engraftment failure/delay are major issues in unrelated umbilical cord blood transplantation (UCBT). We evaluated graft-versus-host disease (GVHD) prophylaxis approaches after UCBT by comparing UCBT outcomes with GVHD prophylaxis using tacrolimus plus methylprednisolone (Tac/mPSL, n = 32) to that with Tac plus methotrexate (Tac/MTX, n = 31) at a single pediatric transplantation center. The 30-day cumulative incidence rates of neutrophil engraftment and median neutrophil engraftment times in the Tac/mPSL and Tac/MTX groups were 70.1% and 90.3% and 19 and 17 days, respectively (p = 0.09). Pre-engraftment immune reactions (PIR) and acute GVHD were improved with Tac/MTX; PIR incidence (p = 0.020) and cumulative incidence of 100-day acute GVHD (grade II–IV, 38.7% vs 68.8%, p = 0.045; grade III–IV, 9.7% vs 34.4%, p = 0.021) were significantly lower in the Tac/MTX group than in the Tac/mPSL group. However, the incidence rates of relapse (p = 0.921) and cytomegalovirus reactivation (p = 0.908), and the estimated overall (p = 0.87) and event-free survival (p = 0.88) were comparable between the two groups. These data indicate that GVHD prophylaxis with Tac/MTX is associated with favorable results, including reduced PIR and acute GVHD incidence after UCBT, without adverse effects.
- Published
- 2019
25. Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells
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Stephanie A. Montgomery, Chuang Sun, Kevin G. Greene, Soldano Ferrone, Gianpietro Dotti, Rahul Mirlekar, Daniel Michaud, Koichi Hirabayashi, Yang Xu, Xingcong Ma, Hongwei Du, Rihe Liu, Cristina R. Ferrone, Sarah Ahn, Silvia Gabriela Herrera, Yuhui Chen, Yuliya Pylayeva-Gupta, Karthik Tiruthani, Jen Jen Yeh, Xinhui Wang, Nancy Porterfield Kren, and Barbara Savoldo
- Subjects
Male ,0301 basic medicine ,Cancer Research ,B7 Antigens ,medicine.medical_treatment ,Cell ,Normal tissue ,Biology ,Immunotherapy, Adoptive ,B7-H1 Antigen ,Article ,Neuroblastoma ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,03 medical and health sciences ,Immune system ,0302 clinical medicine ,CD28 Antigens ,Cancer immunotherapy ,In vivo ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Ovarian Neoplasms ,Receptors, Chimeric Antigen ,Chemistry ,CD28 ,Cell Biology ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Coculture Techniques ,Chimeric antigen receptor ,Tumor Burden ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Haematopoiesis ,medicine.anatomical_structure ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Cancer research ,Female ,Ovarian cancer ,Carcinoma, Pancreatic Ductal ,Signal Transduction - Abstract
The cell surface expression of B7-H3 across multiple tumor subtypes and its restricted expression in normal tissues make it an attractive target for cancer immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts), and tested them in pancreatic ductal adenocarcinoma (PDAC), ovarian cancer (OC) and neuroblastoma (NB) models in vitro and in vivo. The results showed that B7-H3.CAR-Ts effectively controlled the growth of PDAC, OC and NB tumor cells in vitro and in orthotopic, metastatic and patient-derived xenograft (PDX) mouse models. In addition, we found that 4-1BB costimulation promotes lower PD1 expression in B7-H3.CAR-Ts, and thus have superior antitumor activity when targeting PD-L1 constitutively expressing tumor cells. Finally, taking the advantage of the cross-reactivity of B7-H3.CAR with murine B7-H3 (mB7-H3), we investigated the antitumor efficacy and safety of B7-H3.CAR-Ts in a syngeneic pancreatic orthotopic tumor model in immunocompetent mouse. The mB7-H3.CAR-Ts significantly controlled the tumor growth in immunocompetent mice tumor model without decreasing the hematopoietic or immune cell numbers, and no tissue damage in any analyzed organs was observed, these findings further support the safety and efficacy of B7-H3.CAR-Ts for clinical application.
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- 2019
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26. Dendritic Cell-Based Adjuvant Vaccination Targeting Wilms’ Tumor 1 in Patients with Advanced Colorectal Cancer
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Terutsugu Koya, Takashi Kobayashi, Yumiko Mizuno, Kenji Sano, Kenichi Ito, Shigetaka Shimodaira, Tomonobu Koizumi, Naoko Yamaoka, Koichi Hirabayashi, Yumiko Higuchi, and Miki Yuzawa
- Subjects
Oncology ,medicine.medical_specialty ,dendritic cell vaccines ,Wilms’ tumor 1 ,Colorectal cancer ,medicine.medical_treatment ,Immunology ,lcsh:Medicine ,colorectal cancer ,Article ,Metastasis ,tetramer analysis ,Internal medicine ,Drug Discovery ,medicine ,Adjuvant therapy ,Pharmacology (medical) ,Pharmacology ,business.industry ,ELISPOT ,Immunogenicity ,lcsh:R ,Wilms' tumor ,medicine.disease ,Vaccination ,Infectious Diseases ,enzyme-linked immunosorbent spot assay ,immunohistochemistry ,business ,Adjuvant - Abstract
Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.
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- 2015
27. Enzyme-Linked Immunosorbent Spot Assay for the Detection of Wilms’ Tumor 1-Specific T Cells Induced by Dendritic Cell Vaccination
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Naoko Yamaoka, Miki Yuzawa, Terutsugu Koya, Kenji Sano, Yumiko Mizuno, Kiyoshi Yoshizawa, Yumiko Higuchi, Shigetaka Shimodaira, Takashi Kobayashi, and Koichi Hirabayashi
- Subjects
Wilms’ tumor 1 ,Enzyme-linked Immunosorbent Spot Assay ,ELISPOT ,T cell ,Medicine (miscellaneous) ,Context (language use) ,Dendritic cell ,Biology ,antigen-specific cytotoxic T cells ,Peripheral blood mononuclear cell ,Molecular biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,tetramer analysis ,Immune system ,medicine.anatomical_structure ,lcsh:Biology (General) ,enzyme-linked immunosorbent spot assay ,Immunology ,medicine ,Cytotoxic T cell ,dendritic cells ,lcsh:QH301-705.5 - Abstract
Background: Despite recent advances in cancer immunotherapy and the development of various assays for T cell assessment, a lack of universal standards within immune monitoring remains. The objective of this study was to evaluate the enzyme-linked immunosorbent spot (ELISpot) assay in comparison with major histocompatibility complex-tetramer analysis in the context of dendritic cell (DC)-based cancer immunotherapy. Methods: The ELISpot assay was performed on peripheral blood mononuclear cells to assess reproducibility, daily precision, and linearity using HLA-A*24:02-restricted Cytomegalovirus peptide. Wilms’ tumor 1 (WT1) antigen-specific cytotoxic T cells were then evaluated by both the ELISpot assay and WT1 tetramer analysis in peripheral blood from 46 cancer patients who received DC vaccinations pulsed with human leukocyte antigen (HLA)-A*24:02-restricted modified WT1 peptides. Results: The ELISpot assay was proven to have reproducibility (coefficient of variation (CV) ranged from 7.4% to 16.3%), daily precision (CV ranged from 5.0% to 17.3%), and linearity (r = 0.96–0.98). WT1-specific immune responses were detected by the ELISpot assay in 34 out of 46 patients (73.9%) post-vaccination. A Spearman’s rank-correlation coefficient of 0.82 between the ELISpot assay and WT1 tetramer analysis was obtained. Conclusion: This is the first report of a comparison of an ELISpot assay and tetramer analysis in the context of dendritic cell (DC)-based cancer immunotherapy. The ELISpot assay has reproducibility, linearity, and excellent correlation with the WT1 tetramer analysis. These findings suggest that the validated ELISpot assay is useful to monitor the acquired immunity by DC vaccination targeting WT1.
- Published
- 2015
28. Feasibility and Immune Response of WT1 Peptide Vaccination in Combination with OK-432 for Paediatric Solid Tumors
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Shigeo Koido, Masato Okamoto, Ryu Yanagisawa, Koichi Hirabayashi, Terutsugu Koya, Yumiko Higuchi, Shoji Saito, Kenji Sano, Yozo Nakazawa, Shigetaka Shimodaira, and Haruo Sugiyama
- Subjects
Adult ,Male ,0301 basic medicine ,Drug ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,media_common.quotation_subject ,T cell ,medicine.medical_treatment ,Human leukocyte antigen ,Cancer Vaccines ,Picibanil ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Adjuvants, Immunologic ,Neoplasms ,Internal medicine ,medicine ,Humans ,Child ,WT1 Proteins ,media_common ,business.industry ,Vaccination ,General Medicine ,Immunotherapy ,Pediatric cancer ,Immunity, Innate ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,Feasibility Studies ,Female ,business ,Adjuvant - Abstract
Background/aim Wilms' tumor 1 (WT1) peptide-based vaccination has been reported for its potential usefulness in targeting several cancers. The adjuvant drug OK-432 is known to have potent immunomodulation and therapeutic properties when applied in cancer treatment and may, thus, be important to trigger the appropriate immunological response in paediatric patients with a solid tumor that are vaccinated with a WT1 peptide. Patients and methods Paediatric patients with a solid tumor were vaccinated with a WT1 peptide and OK-432 once every 2 weeks, for a total of seven times. Results Of the 24 patients, 18 completed the scheduled vaccinations. Sixteen patients had local skin symptoms and/or fever. In 1 patient, anaphylactic symptoms emerged at the time of the final injection, but these quickly subsided after the treatment. WT1-specific immunological responses were observed in 4 patients (22.2%). WT1 and HLA class I expression were confirmed in 100% and 85% of primary tumors, respectively. Conclusion WT1 peptide vaccine therapy combined with OK-432 appears to be relatively safe for children. However further studies in a larger number of patients are necessary to confirm its safety and efficacy.
- Published
- 2018
29. Ovarian function after allogeneic hematopoietic stem cell transplantation in children and young adults given 8-Gy total body irradiation-based reduced-toxicity myeloablative conditioning
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Takashi Kurata, Miyuki Tanaka, Ryu Yanagisawa, Kazutoshi Komori, Kenichi Koike, Daisuke Morita, Kazuo Sakashita, Yosuke Hara, Yozo Nakazawa, Shoji Saito, and Koichi Hirabayashi
- Subjects
Infertility ,Pediatrics ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,030232 urology & nephrology ,Hematopoietic stem cell transplantation ,030230 surgery ,Primary Ovarian Insufficiency ,Menstruation ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Medicine ,Humans ,Young adult ,Child ,Retrospective Studies ,Transplantation ,Leukemia ,business.industry ,Ovary ,Hematopoietic Stem Cell Transplantation ,Infant ,Total body irradiation ,Myeloablative Agonists ,medicine.disease ,Research Design ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Follicle Stimulating Hormone ,Complication ,business ,Infertility, Female ,Whole-Body Irradiation ,Hormone - Abstract
Background The spectrum of late sequelae after hematopoietic stem cell transplantation (HSCT) includes infertility, which is the most frequent complication. Some reports suggested that ovarian function may be better preserved in females undergoing HSCT with reduced-intensity conditioning (RIC) than with conventional myeloablative conditioning (MAC). However, the impact of HSCT after 8-Gy TBI-based reduced-toxicity MAC (RTMAC), whose efficacy is between those of conventional MAC and RIC, on ovarian function remains unclear. Procedure A single-center retrospective analysis of data derived from patient information for all the children who underwent transplantation at the Shinshu University Hospital was carried out. Patients who underwent 8-Gy total body irradiation (TBI)-based RTMAC before HSCT were analyzed. Results A total of 36% (five of 14) of the patients developed primary ovarian insufficiency (POI) during the observation period, but serum follicle-stimulating hormone levels reduced to normal range with spontaneous menstruation in two, implying the reversal of POI. Furthermore, only one (10%) of the 10 prepubertal patients (71%; 10/14) at the time of HSCT suffered from POI at the last observation, but all three post-pubertal patients developed POI (100%), and two (67%) continued to suffer from POI at the last observation. Conclusions Taken together, 8-Gy TBI-based RTMAC before HSCT may decrease the possibility of POI compared with conventional MAC, especially in prepubertal patients. A longer follow-up will be required to ascertain whether a normal pregnancy and delivery can occur in such patients.
- Published
- 2018
30. Patternmaking of individualized A-line dress using computerized 3D draping method
- Author
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Masayuki Takatera, KyoungOk Kim, and Koichi Hirabayashi
- Subjects
Engineering drawing ,Computer science ,Line (text file) - Published
- 2019
31. Safety and tolerability of allogeneic dendritic cell vaccination with induction of Wilms tumor 1–specific T cells in a pediatric donor and pediatric patient with relapsed leukemia: a case report and review of the literature
- Author
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Haruo Sugiyama, Yumiko Higuchi, Kazuo Sakashita, Kentaro Yoshikawa, Yoshikazu Yonemitsu, Ryu Yanagisawa, Yozo Nakazawa, Shoji Saito, Takashi Kurata, Masaaki Shiohara, Masato Okamoto, Shigetaka Shimodaira, Kenichi Koike, Takashi Kobayashi, Terutsugu Koya, Koichi Hirabayashi, Miyuki Tanaka, and Kiyoshi Yoshizawa
- Subjects
Male ,Cancer Research ,Adolescent ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Cancer Vaccines ,Immune system ,hemic and lymphatic diseases ,medicine ,Humans ,Immunology and Allergy ,Child ,WT1 Proteins ,Adverse effect ,Genetics (clinical) ,Transplantation ,business.industry ,Vaccination ,Hematopoietic Stem Cell Transplantation ,Wilms' tumor ,Dendritic Cells ,Cell Biology ,Dendritic cell ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Peptide Fragments ,Tissue Donors ,Leukemia ,surgical procedures, operative ,Oncology ,Tolerability ,Female ,Neoplasm Recurrence, Local ,Safety ,business - Abstract
A 15-year-old girl with acute lymphoblastic leukemia received allogeneic dendritic cell vaccination, pulsed with Wilms tumor 1 (WT1) peptide, after her third hematopoietic stem cell transplantation (HSCT). The vaccines were generated from the third HSCT donor, who was her younger sister, age 12 years. The patient received 14 vaccines and had no graft-versus-host disease or systemic adverse effect, aside from grade 2 skin reaction at the injection site. WT1-specific immune responses were detected after vaccination by both WT1-tetramer analysis and enzyme-linked immunosorbent spot assay. This strategy may be safe, tolerable and even feasible for patients with a relapse after HSCT.
- Published
- 2015
32. Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction
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Ryu Yanagisawa, Kazuyuki Matsuda, Miyuki Tanaka, Kazuo Sakashita, Kazuki Horiuchi, Shoji Saito, Takashi Kurata, Tomonari Shigemura, Kenichi Koike, Koichi Hirabayashi, and Yozo Nakazawa
- Subjects
Hla class ii ,Bone marrow transplantation ,Hla haplotypes ,business.industry ,Lymphoblastic Leukemia ,medicine.medical_treatment ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Immunology ,Medicine ,business ,Leukemic Blasts ,030215 immunology - Abstract
Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors.
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- 2015
33. Risk factors for diabetes mellitus and impaired glucose tolerance following allogeneic hematopoietic stem cell transplantation in pediatric patients with hematological malignancies
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Takashi Kurata, Yosuke Hara, Miyuki Tanaka, Kenichi Koike, Kanae Hirabayashi, Yozo Nakazawa, Kazuo Sakashita, Kentaro Yoshikawa, Shoji Saito, Ryu Yanagisawa, Koichi Hirabayashi, and Hiroki Matsuura
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,endocrine system diseases ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Overweight ,Gastroenterology ,Impaired glucose tolerance ,Young Adult ,Adipokines ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Glucose Intolerance ,medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Child ,Retrospective Studies ,Adiponectin ,business.industry ,Insulin ,Hematopoietic Stem Cell Transplantation ,Infant ,nutritional and metabolic diseases ,Hematology ,Prognosis ,medicine.disease ,Transplantation ,Glucose ,Treatment Outcome ,Endocrinology ,Diabetes Mellitus, Type 2 ,Child, Preschool ,Hematologic Neoplasms ,Female ,medicine.symptom ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Long-term surviving recipients of allogeneic hematopoietic stem cell transplantation (HSCT) often suffer from diabetes mellitus (DM). We sought to identify risk factors for the development of post-transplant DM and impaired glucose tolerance (IGT) in pediatric HSCT patients. Glucose tolerance statuses were evaluated in 22 patients aged 6.3-21.8 years who had received allogeneic HSCT between the ages of 0.8-13.5 years. Five patients were diagnosed as having type 2 DM, and treated with insulin or oral hypoglycemic agents. Five patients were included in the IGT group, and the remaining 12 children were in the normal glucose tolerance (NGT) group. The cumulative incidence of DM plus IGT was 11.6 % at 5 years and 69.3 % at 10 years. None of the patients were obese/overweight and none had a family history of DM. There were no significant differences in serum levels of leptin and adiponectin between the DM + IGT and the NGT groups. An average preprandial glucose levels in the DM + IGT group were significantly higher than those in the NGT group from preparative conditioning to 60 days after HSCT. In multivariate analysis, an age of ≥6 years at the time of HSCT was significantly associated with the development of DM + IGT. Additionally, careful follow-up is necessary, even for NGT patients.
- Published
- 2014
34. Myeloid progenitors with PTPN11 and nonRAS pathway gene mutations are refractory to treatment with 6-mercaptopurine in juvenile myelomonocytic leukemia
- Author
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Takayuki Honda, Kenichi Koike, C Iwashita, Shoji Saito, Kazuo Sakashita, Yozo Nakazawa, Koichi Hirabayashi, Kentaro Yoshikawa, Takashi Kurata, Kazuyuki Matsuda, Miyuki Tanaka, Ryu Yanagisawa, and Sho Sasaki
- Subjects
Male ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Myeloid ,SETBP1 ,6-MP ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,PTPN11 ,Biology ,Gene mutation ,medicine.disease_cause ,hemic and lymphatic diseases ,medicine ,Humans ,Progenitor cell ,skin and connective tissue diseases ,JMML ,Mutation ,Juvenile myelomonocytic leukemia ,Mercaptopurine ,Infant ,Hematology ,medicine.disease ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Leukemia, Myelomonocytic, Juvenile ,Oncology ,Drug Resistance, Neoplasm ,Child, Preschool ,Immunology ,Neoplastic Stem Cells ,Cancer research ,Female ,JAK3 ,Signal Transduction ,medicine.drug - Abstract
advance online publication, February 25, 2014, Juvenile myelomonocytic leukemia (JMML) is a fatal, mixed myeloproliferative and myelodysplastic disorder occurring in infancy and early childhood. Children with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathways, inactivation of the NF1 or mutations in PTPN11, NRAS, KRAS and CBL. A whole-exome sequencing study, performed by Sakaguchi et al.,3 has recently demonstrated that in addition to the high frequency of RAS pathway mutations, mutations in SETBP1 and JAK3 are common recurrent secondary events, and that these events may be involved in tumor progression, and are associated with poor clinical outcomes., Article, LEUKEMIA. 28(7):1545-1548 (2014)
- Published
- 2014
35. Panobinostat inhibits the proliferation of CD34
- Author
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Takashi, Kurata, Kazuyuki, Matsuda, Koichi, Hirabayashi, Tomonari, Shigemura, Kazuo, Sakashita, Tatsutoshi, Nakahata, and Kenichi, Koike
- Subjects
Male ,Infant ,Antigens, CD34 ,Antineoplastic Agents ,Hematopoietic Stem Cells ,Cell Line ,Mice ,Leukemia, Myelomonocytic, Juvenile ,Child, Preschool ,Panobinostat ,Azacitidine ,Tumor Cells, Cultured ,Animals ,Humans ,Cell Proliferation - Abstract
Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5-azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34We previously reported that stimulation of JMML CD34Panobinostat dose dependently reduced the numbers of day 7 CD34These results demonstrate that panobinostat directly suppresses the growth of JMML CD34
- Published
- 2016
36. In Vivo Administration of Recombinant Human Granulocyte Colony-Stimulating Factor Increases the Immune Effectiveness of Dendritic Cell-Based Cancer Vaccination
- Author
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Tomonobu Koizumi, Terutsugu Koya, Shigetaka Shimodaira, Shigeo Koido, Ryu Yanagisawa, Takashi Kobayashi, Koichi Hirabayashi, Yumiko Higuchi, Misa Togi, Tomohisa Kato, Haruo Sugiyama, and Takuya Sakamoto
- Subjects
0301 basic medicine ,dendritic cell ,medicine.medical_treatment ,Immunology ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Article ,tetramer analysis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Drug Discovery ,Medicine ,Cytotoxic T cell ,Pharmacology (medical) ,030212 general & internal medicine ,Pharmacology ,business.industry ,Immunogenicity ,lcsh:R ,Dendritic cell ,vaccination ,Acquired immune system ,acquired immunity ,030104 developmental biology ,Infectious Diseases ,Cancer vaccine ,granulocyte colony-stimulating factor ,cancer vaccine ,business ,CD80 - Abstract
Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity, however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16&ndash, 18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms&rsquo, tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.
- Published
- 2019
37. Successful cord blood transplantation after repeated transfusions of unmobilized neutrophils in addition to antifungal treatment in an infant with chronic granulomatous disease complicated by invasive pulmonary aspergillosis
- Author
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Taizo Wada, Masaaki Shiohara, Shigetaka Shimodaira, Kenichi Koike, Shoji Saito, Tomonari Shigemura, Norimoto Kobayashi, Kazuo Sakashita, Kentaro Yoshikawa, Yozo Nakazawa, Koichi Hirabayashi, and Kazunaga Agematsu
- Subjects
Voriconazole ,business.industry ,Immunology ,Micafungin ,Hematology ,Cord Blood Stem Cell Transplantation ,medicine.disease ,Chronic granulomatous disease ,Respiratory failure ,Primary immunodeficiency ,medicine ,Absolute neutrophil count ,Immunology and Allergy ,Rituximab ,business ,medicine.drug - Abstract
Background: Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency that affects phagocytic cells. CGD patients are susceptible to fungal infections, especially Aspergillus infections. The management of life-threatening Aspergillus infections in CGD is particularly difficult because some infections cannot be eradicated with standard antifungal treatments and, hence, result in death. Case Report: A 2-week-old girl developed invasive pulmonary aspergillosis, which rapidly progressed to respiratory failure. Liposomal amphotericin B, micafungin, and voriconazole were not effective. At the age of 2 months, she was diagnosed with p67phox-deficient CGD. In addition to antifungal treatment, the patient received 21 granulocyte transfusions (GTX), which were obtained from 300- or 400-mL whole blood samples from healthy random donors who were not treated with granulocyte–colony-stimulating factor or dexamethasone. The median neutrophil count of the GTX was 1.88 × 108/kg body weight. Rituximab was administered to reduce alloimmunization to human leukocyte antigens (HLA) after the eighth GTX, resulting in their absence of anti-HLA before and after cord blood transplantation (CBT). A marked improvement in her invasive pulmonary aspergillosis was achieved, although the first CBT was rejected. Complete hematopoietic recovery was obtained after the second CBT. Conclusion: Repeated GTX containing relatively low doses of neutrophils might be able to control severe Aspergillus infections in infants with CGD.
- Published
- 2013
38. Dendritic Cell-Based Cancer Immunotherapy Targeting Wilms’ Tumor 1 for Pediatric Cancer
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Yumiko Higuchi, Kenji Sano, Ryu Yanagisawa, Tomonobu Koizumi, Koichi Hirabayashi, and Shigetaka Shimodaira
- Subjects
0301 basic medicine ,business.industry ,medicine.medical_treatment ,Cancer ,Wilms' tumor ,Immunotherapy ,Acquired immune system ,medicine.disease ,Pediatric cancer ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Antigen ,030220 oncology & carcinogenesis ,Immunology ,medicine ,business - Abstract
The treatment of advanced pediatric cancers that have metastasized to distant organs remains difficult. Investigations evaluating the potential treatment of these cancers using therapeutic vaccination with an active dendritic cell (DC)-based immunotherapy are also being conducted. This method induces an efficient immune response by the acquired immune system against tumor-associated antigens. Cancer vaccination therapies have been prepared using autologous monocyte-derived mature DCs exposed to granulocyte–macrophage colony-stimulating factor and interleukin-4, which are the molecules principally attributed to the presence of tumor-associated antigens. Wilms’ tumor 1 (WT1), an attractive target antigen that has been widely detected in cancers including sarcoma and leukemia, has been shown to be the most potent tumor-associated antigen. DC-based immunotherapy targeting WT1 may have a potentially strong therapeutic activity against cancers. DC vaccines primed with human leukocyte antigen (HLA) class I-/II-restricted WT1 peptides (WT1-DC) are a feasible option. A 6-year-old girl with neuroblastoma and a 14-year-old girl with WT received autologous DC vaccination pulsed with a modified WT1 peptide compatible with HLA-A*24:02. The patients received 20 and 25 vaccines, respectively, and experienced no adverse effects aside from a grade 2 skin reaction at the injection site and a fever with tolerable elevation. WT1tetramer analysis after vaccination detected WT1-specific immune responses. This treatment strategy may be safe, tolerable, and even feasible for all patients who are refractory to treatment and for pediatric patients who have relapsed with neoplasms.
- Published
- 2016
39. An update on Dendritic Cell-Based Cancer Immunotherapy
- Author
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Shigeo Koido, Terutsugu Koya, Shigetaka Shimodaira, Koichi Hirabayashi, Yumiko Higuchi, Masato Okamoto, and Ryu Yanagisawa
- Subjects
business.industry ,Applied Mathematics ,medicine.medical_treatment ,Immunology ,Cancer ,Immunotherapy ,Dendritic cell ,Human leukocyte antigen ,Acquired immune system ,medicine.disease ,Computer Science Applications ,Immune system ,Computational Theory and Mathematics ,Antigen ,Cancer immunotherapy ,medicine ,business ,Molecular Biology - Abstract
Although treating advanced cancers that affect organs with distant metastasis remains challenging, the pace of recent advances has accelerated; these advances have particularly focused on the inhibitors of key immune potentiates. Research on therapeutic vaccination involving active dendritic cell (DC)-based immunotherapy is also being performed for the induction of an effi cient immune response against cancer-associated antigens by the acquired immune system. Cancer vaccines prepared with autologous monocyte-derived mature DCs have been generated using granulocyte–macrophage colony-stimulating factor and interleukin-4, which are principally attributed to the presence of tumor-associated antigens. Wilms’ tumor 1 (WT1) is an attractive target antigen that is widely detected in many cancers. DC-based immunotherapy targeting WT1 may elicit a strong therapeutic response to cancers. DC vaccines primed with HLA class I/II-restricted WT1 peptides (WT1-DC) are a feasible option for patients with advanced cancers. Immune response monitoring using tetramer analysis and/or enzyme-linked immunosorbent spot assay has been applied to determine the effi cacy of WT1-DC. The inhibition of immune suppressors and acceleration of anti-cancer immunity with WT1-DC may comprise a promising future therapeutic strategy for treating advanced cancers.
- Published
- 2016
40. Standard WT1 Expression Using Immunohistochemistry
- Author
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Yumiko Higuchi, Kenji Sano, Shigetaka Shimodaira, Koichi Hirabayashi, and Terutsugu Koya
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Distant metastasis ,Cancer ,medicine.disease ,030218 nuclear medicine & medical imaging ,Vaccination ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Mrna level ,Cancer immunotherapy ,Antigen ,Cancer research ,Medicine ,Immunohistochemistry ,business ,030217 neurology & neurosurgery - Abstract
Although it remains difficult to treat advanced cancers affecting organs with distant metastasis, therapeutic cancer vaccination is conducted for the induction of an efficient immune response against tumor-associated antigens. Wilms’ tumor 1 (WT1) shown to be the most potent tumor-associated antigens may have potentially strong therapeutic activity against cancers. WT1 expression using immunohistochemistry (IHC) can be evaluated on paraffin-embedded tissues and is proportional to mRNA levels. The standardized IHC would be useful for personalized cancer immunotherapy.
- Published
- 2016
41. Food allergy after cord blood transplantation in children
- Author
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Sawako Kato, Tomonari Shigemura, Kazuo Sakashita, Yozo Nakazawa, Yoshiko Nakayama, Nao Hidaka, Kentaro Yoshikawa, Shoji Saito, Norimoto Kobayashi, Ryu Yanagisawa, Mai Kusakari, Kenichi Koike, Masaaki Shiohara, Koichi Hirabayashi, Mikiko Kobayashi, and Miyuki Tanaka
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,business.industry ,MEDLINE ,Graft vs Host Disease ,Infant ,Retrospective cohort study ,Hematology ,medicine.disease ,Food allergy ,Child, Preschool ,medicine ,Humans ,Female ,Cord Blood Stem Cell Transplantation ,Child ,business ,Food Hypersensitivity ,Cord blood transplantation ,Retrospective Studies - Published
- 2012
42. Critical Illness Polyneuropathy and Myopathy Caused by Bacillus Cereus Sepsis in Acute Lymphoblastic Leukemia
- Author
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Takashi Shimizu, Takefumi Suzuki, Goro Tsuruta, Koichi Hirabayashi, Shoji Saito, Yozo Nakazawa, Yoshihiko Hidaka, Ryu Yanagisawa, Kazuo Sakashita, Miyuki Tanaka, Kenichi Koike, Masaaki Shiohara, and Tetsuhiro Fukuyama
- Subjects
Male ,Adolescent ,Flaccid paralysis ,Multiple Organ Failure ,medicine.medical_treatment ,Electromyography ,Sepsis ,Polyneuropathies ,Bacillus cereus ,Muscular Diseases ,medicine ,Humans ,Critical illness polyneuropathy ,Myopathy ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Septic shock ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Compound muscle action potential ,Oncology ,Anesthesia ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,business - Abstract
We report a pediatric case of critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis during acute lymphoblastic leukemia therapy. A 15-year-old boy developed B. cereus sepsis and multiple organ failure on the 19th day after initiation of chemotherapy, and multidisciplinary treatment was started. Treatment was effective and septic shock with multiple organ failure remitted. He was weaned from a respirator on day 23 after the onset of sepsis, but complete flaccid paralysis of the 4 extremities occurred. His compound muscle action potential and F-wave occurrence were reduced on a nerve conduction test. The number of motor units was markedly decreased, and the amplitude and duration of individual motor units were low and short, respectively, on electromyography. Cerebrospinal fluid was normal. On the basis of these findings, he was diagnosed with critical illness polyneuropathy/myopathy. He underwent intensive rehabilitation and recovered the ability to walk 3 months after onset. He was discharged 1 year after the initiation of chemotherapy, and remission has been maintained without inconvenience to daily living activities for 3 years since disease onset.
- Published
- 2012
43. Panobinostat inhibits the proliferation of CD34+ CD38− cells under stimulation of hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia
- Author
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Kazuo Sakashita, Tatsutoshi Nakahata, Kenichi Koike, Kazuyuki Matsuda, Koichi Hirabayashi, Takashi Kurata, and Tomonari Shigemura
- Subjects
0301 basic medicine ,Juvenile myelomonocytic leukemia ,business.industry ,CD34 ,Stem cell factor ,Hematology ,CD38 ,medicine.disease ,03 medical and health sciences ,Haematopoiesis ,chemistry.chemical_compound ,030104 developmental biology ,Oncology ,chemistry ,Cell culture ,Panobinostat ,Pediatrics, Perinatology and Child Health ,Cancer research ,Medicine ,Stem cell ,business - Abstract
Background Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5-azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34+ cells. Procedure We previously reported that stimulation of JMML CD34+ cells with stem cell factor and thrombopoietin on irradiated murine AGM-S3 cells led to substantial expansion of JMML CD34+ cells that contained leukemic stem cells capable of transplantation into immunodeficient mice. Using this culture system, we evaluated effects of panobinostat and 5-azacytidine on the proliferation of JMML CD34+ cells. Results Panobinostat dose dependently reduced the numbers of day 7 CD34+ cells generated under stimulation of hematopoietic growth factors on AGM-S3 cells in all eight patients with JMML. These patients possessed various genetic and/or karyotypic abnormalities. CD34+ CD38- cells were substantially more sensitive to panobinostat at 10 and 20 nM than CD34+ CD38+ cells. Panobinostat, however, failed to influence the ability of AGM-S3 cells to stimulate JMML CD34+ cell production. In contrast to HL60 cells, apoptosis and cell cycle arrest in panobinostat-mediated inhibition were at low levels in JMML. The inhibitor also suppressed the factor-dependent proliferation of normal CD34+ cells on AGM-S3 cells. Meanwhile, no substantial inhibitory effects of 5-azacytidine on the growth of JMML CD34+ cells were observed. Conclusions These results demonstrate that panobinostat directly suppresses the growth of JMML CD34+ cells, in particular CD34+ CD38- cells, regardless of the genetic abnormality type, suggesting that it is a useful antileukemic drug to target JMML stem cells at a pretransplant stage.
- Published
- 2018
44. Successful induction of therapeutic urinary concentration by intravenous ganciclovir and oral valganciclovir with remission of adenoviral hemorrhagic cystitis after cord blood transplantation
- Author
-
Yoshihiko Katsuyama, Shoji Saito, Kazuo Sakashita, Tomonari Shigemura, Toshimitsu Yanagisawa, Miyuki Tanaka, Koichi Hirabayashi, and Yozo Nakazawa
- Subjects
Ganciclovir ,medicine.medical_specialty ,viruses ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Urine ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Cord blood transplantation ,Transplantation ,business.industry ,Lymphoblastic lymphoma ,virus diseases ,Valganciclovir ,medicine.disease ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,business ,030215 immunology ,Hemorrhagic cystitis ,medicine.drug - Abstract
AdV11-HC is one of the major complications after allogeneic HSCT in Japan. We previously reported that the intravenous infusion of ganciclovir was effective against AdV11-HC in a post-transplant patient. We here report a case of a 10-year-old boy who underwent cord blood transplantation for the treatment of relapsed lymphoblastic lymphoma. He developed AdV11-HC with an elevated AdV load in his urine and blood on day 14 after HSCT. He was immediately treated with intravenous ganciclovir; he rapidly achieved a remission of AdV11-HC with a decreased AdV load in his urine and blood. He remained in remission of AdV11-HC, even after we switched ganciclovir to oral valganciclovir on day 63. A pharmacokinetics study of his urine revealed that therapeutic concentrations of ganciclovir could be achieved by both intravenous ganciclovir and oral valganciclovir. These findings suggested that both intravenous ganciclovir and oral valganciclovir could be promising alternatives for the treatment of AdV11-HC in post-transplant patients.
- Published
- 2018
45. Clinical and laboratory outcomes after umbilical cord blood transplantation in a patient with mucolipidosis II alpha/beta
- Author
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Shoji Saito, Masaaki Shiohara, Kaori Adachi, M Takagi, Kenichi Koike, Norio Sakai, Yozo Nakazawa, Takumi Shibazaki, Kazuo Sakashita, Tomonari Shigemura, Koichi Hirabayashi, and Eiji Nanba
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Immunoglobulins ,Transferases (Other Substituted Phosphate Groups) ,Cord Blood Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Mucolipidoses ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Abnormalities, Multiple ,Cyclophosphamide ,Genetics (clinical) ,Umbilical Cord Blood Transplantation ,Mucolipidosis ,business.industry ,Total body irradiation ,medicine.disease ,Transplantation ,surgical procedures, operative ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cord blood ,Child, Preschool ,Immunology ,Female ,Rabbits ,Psychomotor Disorders ,Psychomotor disorder ,business ,Vidarabine - Abstract
Mucolipidosis (ML) II alpha/beta is an autosomal recessive disease caused by reduced enzyme activity of N-acetylglucosamine-1-phosphotransferase. Clinical symptoms of ML II are severe psychomotor delay and dysostosis multiplex; death usually occurs by 5-8 years of age from cardiopulmonary complications. Allogeneic hematopoietic stem cell transplantation (HSCT) has been attempted for ML; however, few reports have documented the detailed outcomes of HSCT for ML. A 26-month-old girl received a human leukocyte antigen 3/6-allele-matched transplant from cord blood. The preparative regimen consisted of fludarabine, cyclophosphamide, 6-Gy total body irradiation, and rabbit antithymocyte globulin. Although comparing before and after cord blood transplantation results, we observed that lysosomal enzyme activities in the plasma decreased by approximately 20-40%. Low serum levels of immunoglobulin A, G2, and G4 were also observed before HSCT; however, these values normalized after transplantation. Despite undergoing HSCT, she was treated twice for bacterial pneumonia with acute respiratory distress syndrome at ages 37 and 38 months. Although HSCT effects on the clinical manifestations were limited, laboratory data including plasma lysosomal enzyme activities and serum levels of immunoglobulin showed improvement.
- Published
- 2015
46. Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction
- Author
-
Koichi, Hirabayashi, Takashi, Kurata, Kazuki, Horiuchi, Shoji, Saito, Tomonari, Shigemura, Miyuki, Tanaka, Ryu, Yanagisawa, Kazuyuki, Matsuda, Kazuo, Sakashita, Kenichi, Koike, and Yozo, Nakazawa
- Subjects
Male ,Hematopoietic Stem Cell Transplantation ,Histocompatibility Antigens Class II ,Graft vs Host Disease ,Infant ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Haplotypes ,Histocompatibility ,HLA-DQ beta-Chains ,Humans ,Female ,Neoplasm Recurrence, Local ,Child ,Alleles ,HLA-DP beta-Chains ,HLA-DRB1 Chains - Abstract
Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors.
- Published
- 2015
47. Future Prospective of Cancer Vaccination Technology in Japan
- Author
-
Takashi Kobayashi, Yumiko Higuchi, Kiyoshi Yokokawa, Koichi Hirabayashi, and Shigetaka Shimodaira
- Subjects
business.industry ,medicine.medical_treatment ,Cancer ,Immunotherapy ,medicine.disease ,Regulatory affairs ,Cell therapy ,Radiation therapy ,Vaccination ,Clinical trial ,Pancreatic cancer ,Immunology ,medicine ,business - Abstract
Dendritic cell (DC)-based immunotherapy has been developed against various types of cancers. To develop and promote regenerative medicine and cell therapy in Japan, the Act on the Safety of Regenerative Medicine and the Revised Pharmaceutical Affairs Law have been enforced since November 25, 2014. Therapeutic vaccination with active DCs was evaluated under the legal framework. Cancer vaccination therapies with autologous monocyte-derived mature DCs are principally attributed to the presence of tumor-associated antigens. Clinical studies and trials should be conducted in accordance with legislation for approval of either DC-based cancer therapy or DC vaccine products. The following issues with regards to DC-based vaccination and vaccine products for clinical use may be raised: 1) Manufacturing of DCs according to the standard grade of Good Gene, Cellular, and Tissue-based Products (GCTP) Manufacturing Practice; 2) Peptides that target cancer-associated antigens for any cancer patient; 3) Quality of immunological analyses as proof of concept; and 4) Optimization of DC vaccines as add-ons to chemotherapeutic drugs and/or radiotherapy to predict potential biomarkers of response. Phase II clinical trials that are covered by Advanced Medical Care System would be conducted on DC vaccine pulsed with Wilms’ tumor 1-specific MHC class I/II-restricted epitopes for pancreatic cancer. The designed clinical trial adopted with new technology could reveal the efficacy of DC vaccine in combination with optimized therapies. This would be relevant to the development of personalized therapy in cancer patients.
- Published
- 2015
48. Induction of Antigen-Specific Cytotoxic T Lymphocytes by Chemoradiotherapy in Patients Receiving Wilms? Tumor 1-Targetted Dendritic Cell Vaccinations for Pancreatic Cancer
- Author
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Miki Yuzawa, Kayo Horiuchi, Shigetaka Shimodaira, and Tomonobu Koizumi, Naoko Yamaoka, S Ishikawa, Takashi Kobayashi, Yumiko Higuchi, Yumiko Mizuno, Terutsugu Koya, Koichi Hirabayashi, Kenichi Ito, and Kenji Sano
- Subjects
business.industry ,ELISPOT ,Cancer ,Human leukocyte antigen ,Dendritic cell ,Acquired immune system ,medicine.disease ,Pancreatic cancer ,Immunology ,Cancer research ,Medicine ,Cytotoxic T cell ,business ,Chemoradiotherapy - Abstract
Despite recent advances in cancer treatment, the prognosis of pancreatic cancer (PC) remains poor. Dendritic cells (DCs) play a central role in acquired immunity; therapeutic DC vaccinations have recently been developed for advanced PC. Here we present two cases of PC: inoperable PC localized to the pancreatic head (Case 1, stage IV) and local recurrence complicated by distant metastases following resection of the pancreas body and tail (Case 2, stage III). Both patients received DC vaccinations pulsed with human leukocyte antigen (HLA)-Class I/II-restricted Wilms’ tumor 1 (WT1) peptides during chemoradiotherapy. The induction of WT1 antigen-specific cytotoxic T cells (WT1-CTL) was markedly increased by chemoradiotherapy and was confirmed by measurement of WT1 tetramers and enzyme-linked immunosorbent spot (ELISpot) in both cases. WT1-CTL was found to persist at 1 year without additional DC vaccines in Case 1. In cases 1 and 2, the overall survival (OS) was 32.1 and 24.7 months, respectively, and progression-free survival (PFS) was 25.2 and 8.7 months, respectively. Adverse reactions due to the DC vaccination were tolerable even during chemoradiotherapy, resulting in disease stability. The findings of the present cases may form treatment strategies involving DC vaccination for PC.
- Published
- 2015
49. Acute Respiratory Distress Syndrome Caused by Ingestion of a Toilet-Bowl Cleaner Containing Sodium Hypochlorite
- Author
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Hiroshi Imamura, Koichi Hirabayashi, Tomomi Iwashita, Satoshi Toba, Yukio Sekiguchi, and Kazufumi Okamoto
- Subjects
Toilet ,medicine.medical_specialty ,chemistry.chemical_compound ,chemistry ,business.industry ,Anesthesia ,Sodium hypochlorite ,medicine ,Ingestion ,Acute respiratory distress ,Intensive care medicine ,business - Abstract
次亜塩素酸ナトリウム(SHC)を含むトイレ漂白剤飲用後の消化器障害の報告は多い。しかし,急性呼吸促迫症候群(ARDS)の報告はまれである。症例は72歳の女性。SHCを含むトイレ漂白剤を自殺目的で飲み,近医にて処置後,本院へ搬送された。来院時,口腔などの発赤と両肺野に水泡性ラ音を認めた。気管挿管下での人工呼吸管理を開始したが,入院8時間後にはPaO2/FIO2は185mmHgと低下し,胸部X線上両肺野の浸潤影を認めた。ARDSに対しシベレスタットナトリウムの投与を開始し,第8病日には人工呼吸器を離脱できた。SHCは誤嚥による直接的な腐食による化学性肺炎からARDSを起こす可能性があるだけでなく,塩酸や塩素ガスを発生しARDSを起こす可能性がある。さらに,SHCそのものが肺組織内の還元型グルタチオンを枯渇させARDS引き起こす可能性もある。SHC飲用例ではARDSの発症に十分な注意が必要である。
- Published
- 2006
50. Reduced-toxicity myeloablative conditioning consisting of 8-Gy total body irradiation, cyclophosphamide and fludarabine for pediatric hematological malignancies
- Author
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Yozo Nakazawa, Shoji Saito, Takashi Kurata, Ryu Yanagisawa, Kazuo Sakashita, Kentaro Yoshikawa, Miyuki Tanaka, Kenichi Koike, and Koichi Hirabayashi
- Subjects
Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,Cyclophosphamide ,medicine.medical_treatment ,Graft vs Host Disease ,Myeloablative Agonist ,Hematopoietic stem cell transplantation ,Gastroenterology ,Article ,Young Adult ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Child ,Retrospective Studies ,Leukemia ,Multidisciplinary ,Juvenile myelomonocytic leukemia ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Infant ,Myeloablative Agonists ,Total body irradiation ,medicine.disease ,Survival Analysis ,Fludarabine ,Surgery ,Regimen ,Gamma Rays ,Child, Preschool ,Myelodysplastic Syndromes ,Quality of Life ,Female ,business ,Vidarabine ,Whole-Body Irradiation ,medicine.drug - Abstract
Conventional myeloablative conditioning (MAC) regimens often cause severe regimen-related toxicity (RRT). Furthermore, many patients suffer from poor quality of life in accordance with the increase in long-term survivors. We therefore devised a reduced-toxicity myeloablative conditioning (RTMAC) regimen consisting of 8-Gy total body irradiation (TBI), fludarabine (FLU) and cyclophosphamide (CY) for pediatric hematological malignancies. A retrospective single-center analysis was performed on patients with leukemia or myelodysplastic syndrome (MDS), aged ≤20 years, who had received an 8-Gy TBI/FLU/CY RTMAC regimen followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thirty-one patients underwent first allo-HSCT after an RTMAC regimen. The diagnoses were acute lymphoblastic leukemia (n = 11), acute myeloid leukemia (n = 13), MDS (n = 4), juvenile myelomonocytic leukemia (n = 1) and acute leukemias of ambiguous lineage (n = 2). While 3 patients showed early hematological relapse, the remaining 28 patients achieved engraftments. None of the patients developed grade 4 or 5 toxicities during the study period. The 5-year overall survival and relapse-free survival were 80% [95% confidence interval: CI, 61–91%] and 71% [95% CI, 52–84%], respectively. Our RTMAC regimen would be less toxic and offers a high probability of survival for children with hematological malignancies.
- Published
- 2014
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