Molecular basis for KIR ligand-mismatched cord blood transplantation for advanced neuroblastoma

• Project/Area Number: 18H02690
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Nagoya University
• Principal Investigator: Takahashi Yoshiyuki 名古屋大学, 医学系研究科, 教授 (40432273)
• Co-Investigator(Kenkyū-buntansha): 門松 健治 名古屋大学, 医学系研究科, 教授 (80204519) ; 上條 岳彦 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 所長 (90262708)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 神経芽腫 / がん免疫 / PDX

Outline of Final Research Achievements

We were able to establish a Patient-derived Tumor Xenograft (PDX) model using tumors derived from neuroblastoma patients, and established PDX libraries in 5 cases from 18 neuroblastoma patients. Our established PDX model is used in the multicenter prospective clinical study (JN-H-20) nationwide.

Academic Significance and Societal Importance of the Research Achievements

これまで神経芽腫患者由来の腫瘍細胞を直接研究に使うことが困難であったが、異種移植（Patient-derived Tumor Xenograft, PDX）モデルを確立でき、18例の神経芽腫患者の生検材料より5例でPDXライブラリを樹立できた。さらに全国で進行期神経芽腫に対する前向き多施設共同研究（JN-H-20）に登録した患者よりPDXライブラリの樹立を行い、薬剤スクリーニングやがん免疫療法の有効性確認に利用できる基盤整備ができ検体の収集を開始できた。KIR2DL1単独陽性NK細胞が同種臍帯血移植後1年かけて徐々に増加して神経芽腫に効果を示すメカニズムを解明した。

Research Products

• [Journal Article] Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide (2020)
  • Author(s): Yoshida Nao、Takahashi Yoshiyuki、Yabe Hiromasa、Kobayashi Ryoji、Watanabe Kenichiro、Kudo Kazuko、Yabe Miharu、Miyamura Takako、Koh Katsuyoshi、Kawaguchi Hiroshi、Goto Hiroaki、Fujita Naoto、Okada Keiko、Okamoto Yasuhiro、Kato Koji、Inoue Masami、Suzuki Ritsuro、Atsuta Yoshiko、Kojima Seiji
  • Journal Title: Bone Marrow Transplantation Volume: 55 Issue: 7 Pages: 1272-1281
  • DOI: 10.1038/s41409-020-0948-8
  • Peer Reviewed
• [Journal Article] Detection of subclonal SETBP1 and JAK3 mutations in juvenile myelomonocytic leukemia using droplet digital PCR (2020)
  • Author(s): Wakamatsu Manabu、Okuno Yusuke、Murakami Norihiro、Miwata Shunsuke、Kitazawa Hironobu、Narita Kotaro、Kataoka Shinsuke、Ichikawa Daisuke、Hamada Motoharu、Taniguchi Rieko、Suzuki Kyogo、Kawashima Nozomu、Nishikawa Eri、Narita Atsushi、Nishio Nobuhiro、Kojima Seiji、Muramatsu Hideki、Takahashi Yoshiyuki
  • Journal Title: Leukemia Volume: 35 Issue: 1 Pages: 259-263
  • DOI: 10.1038/s41375-020-0817-x
  • Peer Reviewed
• [Journal Article] Clinical Characteristics and Treatment Outcomes of Pediatric Patients with Non-Hodgkin Lymphoma in East Asia (2020)
  • Author(s): Suh Jin Kyung、Gao Yi-Jin、Tang Jing-Yan、Jou Shiann-Tarng、Lin Dong-Tsamn、Takahashi Yoshiyuki、Kojima Seiji、Jin Ling、Zhang Yonghong、Seo Jong Jin
  • Journal Title: Cancer Research and Treatment Volume: 52 Issue: 2 Pages: 359-368
  • DOI: 10.4143/crt.2019.219
  • Peer Reviewed
• [Journal Article] Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases (2020)
  • Author(s): Umeda K, Imai K, Yanagimachi M, Yabe H, Kobayashi M, Takahashi Y, Kajiwara M, Yoshida N, Cho Y, Inoue M, Hashii Y, Atsuta Y, Morio T
  • Journal Title: Int J Hematol Volume: - Issue: 6 Pages: 869-876
  • DOI: 10.1007/s12185-020-02839-4
  • Peer Reviewed / Open Access
• [Journal Article] Combination of tumor necrosis factor‐α and epidermal growth factor induces the adrenergic‐to‐mesenchymal transdifferentiation in SH‐SY5Y neuroblastoma cells (2020)
  • Author(s): Huang Yue、Tsubota Shoma、Nishio Nobuhiro、Takahashi Yoshiyuki、Kadomatsu Kenji
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 715-724
  • DOI: 10.1111/cas.14760
  • Peer Reviewed
• [Journal Article] Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model (2020)
  • Author(s): Tanaka Kuniaki、Kato Itaru、Tanaka Miyuki、Morita Daisuke、Matsuda Kazuyuki、Takahashi Yoshiyuki、Nakahata Tatsutoshi、Umeda Katsutsugu、Hiramatsu Hidefumi、Adachi Souichi、Takita Junko、Nakazawa Yozo
  • Journal Title: Molecular Therapy - Oncolytics Volume: 18 Pages: 37-46
  • DOI: 10.1016/j.omto.2020.05.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study. (2020)
  • Author(s): Suzuki T, Kawada JI, Nishikawa E, Torii Y, Horiba K, Takeuchi S, Okumura T, Muramatsu H, Takahashi Y, Ito Y
  • Journal Title: Bone Marrow Transplant Volume: - Issue: 9 Pages: 1872-1874
  • DOI: 10.1038/s41409-020-0867-8
  • Peer Reviewed / Open Access
• [Journal Article] Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program. (2020)
  • Author(s): Kobayashi R, Inoue M, Takahashi Y, Kikuta A, Ogawa A, Koga Y, Koh K, Hashii Y, Hara J, Kato K, Tabuchi K, Matsumoto K
  • Journal Title: J Pediatr Hematol Oncol Volume: - Issue: 4 Pages: 251-255
  • DOI: 10.1097/mph.0000000000001779
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia: A Report from the Japan Society for Hematopoietic Cell Transplantation. (2019)
  • Author(s): Yoshida N, Sakaguchi H, Yabe M, Hasegawa D, Hama A, Hasegawa D, Kato M, Noguchi M, Terui K, Takahashi Y, Cho Y, Sato M, Koh K, Kakuda H, Shimada H, Hashii Y, Sato A, Kato K, Atsuta Y, Watanabe K; Pediatric Myelodysplastic Syndrome Working Group of the Japan Society for Hematopoietic Cell Transplantation.
  • Journal Title: Biol Blood Marrow Transplant Volume: S1083-8791 Issue: 5 Pages: 30835-3
  • DOI: 10.1016/j.bbmt.2019.11.029
  • Peer Reviewed / Open Access
• [Journal Article] MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome (2019)
  • Author(s): Kato Kohji、Miya Fuyuki、Hamada Nanako、Negishi Yutaka、Narumi-Kishimoto Yoko、Ozawa Hiroshi、Ito Hidenori、Hori Ikumi、Hattori Ayako、Okamoto Nobuhiko、Kato Mitsuhiro、Tsunoda Tatsuhiko、Kanemura Yonehiro、Kosaki Kenjiro、Takahashi Yoshiyuki、Nagata Koh-ichi、Saitoh Shinji
  • Journal Title: Journal of Medical Genetics Volume: 印刷中 Issue: 6 Pages: 388-395
  • DOI: 10.1136/jmedgenet-2018-105487
  • Peer Reviewed / Open Access
• [Journal Article] Human herpesvirus-6B infection in pediatric allogenic hematopoietic stem cell transplant patients: Risk factors and encephalitis. (2019)
  • Author(s): Miura H, Kawamura Y, Hattori F, Tanaka M, Kudo K, Ihira M, Yatsuya H, Takahashi Y, Kojima S, Sakaguchi H, Yoshida N, Hama A, Yoshikawa T
  • Journal Title: Transpl Infect Dis Volume: 22 Issue: 1
  • DOI: 10.1111/tid.13203
  • Peer Reviewed / Open Access
• [Journal Article] Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR (2018)
  • Author(s): Hamada Motoharu、Nishio Nobuhiro、Okuno Yusuke、Suzuki Satoshi、Kawashima Nozomu、Nakazawa Yozo、Takahashi Yoshiyuki、et al
  • Journal Title: EBioMedicine Volume: 34 Pages: 18-26
  • DOI: 10.1016/j.ebiom.2018.07.008
  • Peer Reviewed / Open Access
• [Journal Article] Integrated molecular profiling of juvenile myelomonocytic leukemia (2018)
  • Author(s): Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H
  • Journal Title: Blood Volume: 131 Issue: 14 Pages: 1576-1586
  • DOI: 10.1182/blood-2017-07-798157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] piggyBacトランスポゾン法によるCAR-T細胞療法の開発 (2020)
  • Author(s): 高橋義行
  • Organizer: 第12回日本血液疾患免疫療法学会
• [Presentation] 細胞で子どものがんを治すはなし (2020)
  • Author(s): 高橋義行
  • Organizer: 名古屋大学 ミニ・オープンレクチャー2020
• [Presentation] 治療後に腫瘍が残存している中間リスク神経芽腫患者の良好な予後 (2020)
  • Author(s): Nobuhiro Nishio, Daisuke Ichikawa, Motoharu Hamada, Eri Nishikawa, Nozomu Kawashima, Atsushi Narita, Hideki Muramatsu, Seiji Kojima, Yoshiyuki Takahashi.
  • Organizer: 第62回日本小児血液・がん学会学術集会
• [Presentation] CAR-T細胞によるがん治療 ～細胞で命を救う～ (2020)
  • Author(s): 高橋義行
  • Organizer: J-TEC 再生医療の今を知るオンラインセミナー
• [Presentation] がん撲滅サミット公開セカンドオピニオン～患者ファーストの医療を確立せよ！～ (2020)
  • Author(s): 高橋義行
  • Organizer: 日米がん撲滅サミット2020
  • Int'l Joint Research
• [Presentation] 小児がん・白血病に対するがん免疫療法 (2020)
  • Author(s): 高橋義行
  • Organizer: 第11回日本がん・生殖医療学会学術集会
• [Presentation] 小児固形腫瘍に対する同種移植の可能性 (2020)
  • Author(s): 高橋義行
  • Organizer: 第43回日本造血細胞移植学会
• [Presentation] 小児再発・難治神経芽腫の自家末梢血幹細胞採取におけるプレリキサホル有効性に関する検討 (2020)
  • Author(s): 濱田太立, 成田 敦, 今屋雅之, 山森彩子, 吉田太郎, 若松 学, 三輪田俊介, 成田幸太郎, 川島 希, 谷口理恵子, 西川英里, 西尾信博, 村松秀城, 高橋義行.
  • Organizer: 第43回日本造血細胞移植学会
• [Presentation] 小児高リスク転移性神経芽腫に対するKIRリガンド不一致同種臍帯血移植におけるGraft-versus-tumor effect (2020)
  • Author(s): 西尾信博, 市川大輔, 山森彩子, 若松 学, 成田幸太郎, 吉田太郎, 今屋雅之, 三輪田俊介, 谷口理恵子, 濱田太立, 西川英里, 川島 希, 奥野友介, 成田 敦, 村松秀城, 小島勢二, 高橋 義行
  • Organizer: 第43回日本造血細胞移植学会
• [Presentation] 非ウイルスベクター法を用いたキメラ抗原受容体遺伝子導入Ｔ細胞（CAR-T 細胞）療法の現状と展望 (2019)
  • Author(s): 高橋義行
  • Organizer: 第30回日本医学会総会2019中部
  • Invited
• [Presentation] 転移性高リスク神経芽腫に対するがん免疫療法の最前線 (2019)
  • Author(s): 高橋義行
  • Organizer: 第68回神奈川小児腫瘍研究会
  • Invited
• [Presentation] PiggyBac transposon mediated gene modified T cell therapy for cost-effective therapeutic platform against cancer (2019)
  • Author(s): Yoshiyuki Takahashi
  • Organizer: 第57回日本癌治療学会学術集会
  • Invited
• [Presentation] CAR-T細胞療法の基礎と臨床 (2019)
  • Author(s): 高橋義行
  • Organizer: 第61回日本小児血液・がん学会学術集会
  • Invited
• [Presentation] Chimeric antigen receptor (CAR) T cell therapy with non-virus vector system (2019)
  • Author(s): Yoshiyuki Takahashi
  • Organizer: Insights in Hematology conference 2019
  • Int'l Joint Research / Invited
• [Presentation] がん治療の最前線 CAR-T細胞療法 (2019)
  • Author(s): 高橋義行
  • Organizer: 第30回日本医療薬学会年会
  • Invited
• [Presentation] 急性リンパ性白血病に対する非ウイルスベクター法を用いたCAR-T細胞療法の開発 (2019)
  • Author(s): 高橋義行
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] Clinical trial of KIR-ligand incompatible allogeneic cord blood transplantation reduces relapse of bone marrow in children with primary high risk stage 4 neuroblastoma. (2019)
  • Author(s): Yoshiyuki Takahashi.
  • Organizer: 第41回造血細胞移植学会総会
  • Invited
• [Presentation] Evalution of complication in cord blood transplantation from KIR ligand incompatible donor. (2019)
  • Author(s): Atsushi Narita, Shunsuke Miwata, Kotaro Narita, Hironobu Kitazawa, Shinsuke Kataoaka, Motoharu Hamada, Rieko Taniguchi, Daisuke Ichikawa, Norihiro Murakami, Kyogo Suzuki, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, Seiji Kojima, Yoshinori Ito, Takahahsi Yoshiyuki.
  • Organizer: 第41回造血細胞移植学会総会
• [Presentation] KIR-ligand incompatible allogeneic cord blood transplantation for relapsed stage 4 neuroblastoma in a multicenter trial. (2018)
  • Author(s): Kataoka S, Nishio N, Arakawa Y, Kakuda H, Kuroda H, Ito E, Hyakuna N, Kobayashi M, Takahashi Y.
  • Organizer: Advandces in Neutroblastoma Reseah Association
  • Int'l Joint Research
• [Presentation] 再発4期神経芽腫に対するKIRリガンド不一致同種臍帯血移植の多施設共同研究による治療成績 (2018)
  • Author(s): 片岡伸介, 西尾信博, 荒川ゆうき, 角田治美, 黒田啓史, 伊藤悦朗, 百名伸之, 小林正夫, 高橋義行
  • Organizer: 第10回血液疾患免疫療法学会学術集会（SIHDS 2018）
• [Presentation] 骨髄MRDの消失は神経芽腫に対するKIRリガンド不一致同種臍帯血移植後の移植片対腫瘍効果を示唆する (2018)
  • Author(s): Nobuhiro Nishio, Shinsuke Kataoka, Shunsuke Miwata, Kotaro Narita, Hironobu Kitazawa, Motoharu Hamada, Daisuke Ichikawa, Rieko Taniguchi, Norihiro Murakami, Kyogo Suzuki, Nozomu Kawashima, Eri Nishikawa, Yusuke Okuno, Atsushi Narita, Hideki Muramatsu, Seiji Kojima, Yoshiyuki Takahashi.
  • Organizer: 第60回日本小児血液・がん学会学術集会