Study of HLA-haploidentical stem cell transplantation that enables high graft-versus-leukemia effects

• Project/Area Number: 16K09882
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hyogo Medical University
• Principal Investigator: OGAWA Hiroyasu 兵庫医科大学, 医学部, 名誉教授 (80194447)
• Co-Investigator(Kenkyū-buntansha): 岡田 昌也 兵庫医科大学, 医学部, 講師 (00309452) ; 海田 勝仁 兵庫医科大学, 医学部, 助教 (00441254) ; 井上 貴之 兵庫医科大学, 医学部, 助教 (20441256)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HLA半合致移植 / 移植片対白血病効果 / 移植片対宿主病 / 白血病 / サイトカイン / GVHD / GVL / GVL効果 / MHC半合致移植 / 造血幹細胞移植学

Outline of Final Research Achievements

We developed originally an HLA-haploidentical stem cell transplantation, which exerts a strong graft-versus-leukemia (GVL) effect. To clarify the mechanism, we originally established a haploidentical murine BMT model. Using the model, we showed a prophylactic dexamethasone (Dex) treatment suppressed GVHD with preserving GVL effects. In secondary lymphoid organs that cause GVH reaction, donor T cells grew by antigen-driven proliferation, and Dex suppressed donor T cell proliferation completely through suppressing the activation of dendritic cells. On the other hands, in bone marrow (BM), in which GVL effects occur, donor T cells were found to grow through homeostatic proliferation, which was not affected by Dex. Furthermore, we demonstrated that donor T cells proliferating in the BM had anti-leukemic effects in in-vitro study. In conclusion, we found that the differences in proliferation style of donor T cells resulted in exerting GVL effects not accompanied by GVH reactions.

Academic Significance and Societal Importance of the Research Achievements

HLA半合致移植で高いGVL効果が得られる機序を明らかにすることによって、非寛解期症例にも有効な新しい移植療法の実現が期待され、現在、救命できていない50-60%の治療抵抗性の患者の救命に貢献できるものと考える。HLA半合致移植のGVHDを制御できるということが、現時点で、世界的な造血幹細胞移植の到達地点であるが、本研究では、その先を行き、HLA半合致移植片のアロ免疫の強さに注目し、それを逆手にとり、治療抵抗性血液腫瘍を治そうという新しい発想の研究である。よって、細胞療法の分野で、HLA適合移植からHLA不適合移植への大きなパラダイムシフトをもたらす可能性があると考えている。

Research Products

• [Journal Article] Low incidence of HHV‐6 reactivation in haploidentical hematopoietic stem cell transplantation with corticosteroid as graft‐vs‐host disease prophylaxis compared with cord blood transplantation (2019)
  • Author(s): Tamaki Hiroya、Ikegame Kazuhiro、Yoshihara Satoshi、Kaida Katsuji、Yoshihara Kyoko、Inoue Takayuki、Kato Ruri、Nakata Jun、Fujioka Tatsuya、Soma Toshihiro、Okada Masaya、Ogawa Hiroyasu
  • Journal Title: Transplant Infectious Disease Volume: - Issue: 3
  • DOI: 10.1111/tid.13073
  • Peer Reviewed
• [Journal Article] High probability of follow-up termination among AYA survivors after allogeneic hematopoietic cell transplantation. (2019)
  • Author(s): Miyamura K, Yamashita T, Atsuta Y, Ichinohe T, Kato K, Uchida N, Fukuda T, Ohashi K, Ogawa H, Eto T, Inoue M, Takahashi S, Mori T, Kanamori H, Yabe H, Hama A, Okamoto S, Inamoto Y.
  • Journal Title: Blood Adv. Volume: 12 Issue: 3 Pages: 397-405
  • DOI: 10.1182/bloodadvances.2018026039
  • Peer Reviewed
• [Journal Article] Clinical significance of low-dose total body irradiation in HLA-mismatched reduced-intensity stem cell transplantation. (2019)
  • Author(s): Fujiwara SI, Kanda J, Tatara R, Ogawa H, Fukuda T, Okumura H, Ohashi K, Iwato K, Ueda Y, Ishiyama K, Eto T, Matsuoka KI, Nakamae H, Onizuka M, Atsuta Y, Kanda Y.
  • Journal Title: Bone Marrow Transplant. Volume: 印刷中 Issue: 8 Pages: 1327-1336
  • DOI: 10.1038/s41409-019-0434-3
  • Peer Reviewed
• [Journal Article] A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia-lymphoma. (2019)
  • Author(s): Yoshimitsu M, Utsunomiya A, Fuji S, Fujiwara H, Fukuda T, Ogawa H, Takatsuka Y, Ishitsuka K, Yokota A, Okumura H, Ishii K, Nishikawa A, Eto T, Yonezawa A, Miyashita K, Tsukada J, Tanaka J, Atsuta Y, Kato K.
  • Journal Title: Bone Marrow Transplant. Volume: 印刷中 Issue: 8 Pages: 1266-1274
  • DOI: 10.1038/s41409-018-0400-5
  • Peer Reviewed / Open Access
• [Journal Article] Impact of pretransplant leukemic blast% in bone marrow and peripheral blood on transplantation outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation in non-CR. (2018)
  • Author(s): Ogawa H, Ikegame K, Daimon T, Uchida N, Fukuda T, Kakihana K, Eto T, Ozawa Y, Kanamori H, Hidaka M, Iwato Y, Ichinohe T, Takanashi M, Atsuta Y, Kanda Y
  • Journal Title: Bone Marrow Transplantation Volume: 53 Issue: 4 Pages: 478-482
  • DOI: 10.1038/s41409-017-0028-x
  • Peer Reviewed
• [Journal Article] A prospective multicenter phase II study of intrabone marrow transplantation of unwashed cord blood using reduced-intensity conditioning. (2018)
  • Author(s): Okada M, Tasaka T, Ikegame K, Aotsuka N, Kobayashi T, Najima Y, Matsuhashi Y, Wada H, Tokunaga H, Masuda S, Utsu Y, Yoshihara S, Kaida K, Daimon T, Ogawa H.
  • Journal Title: European Journal of Haematology Volume: 100 Pages: 335-343
  • Peer Reviewed
• [Journal Article] Fatigue, Muscle Oxygen Consumption and Blood Flow to the Skeletal Muscle After Allogeneic Hematopoietic Stem Cell Transplantation. (2018)
  • Author(s): Morishita S, Wakasugi T, Kaida K, Itani Y, Ikegame K, Ogawa H, Domen K.
  • Journal Title: Adv Exp Med Biol. Volume: 1072 Pages: 293-298
  • DOI: 10.1007/978-3-319-91287-5_47
  • ISBN: 9783319912851, 9783319912875
  • Peer Reviewed
• [Journal Article] Hemoglobin Dynamics in the Skeletal Muscle of Patients with Malignant Hematopoietic Disease. (2018)
  • Author(s): Wakasugi T, Morishita S, Kaida K, Itani Y, Kodama N, Ikegame K, Ogawa H, Domen K.
  • Journal Title: Adv Exp Med Biol. Volume: 1072 Pages: 287-291
  • DOI: 10.1007/978-3-319-91287-5_46
  • ISBN: 9783319912851, 9783319912875
  • Peer Reviewed
• [Journal Article] Impact of a low CD34 dose on allogeneic peripheral blood stem cell transplantation. (2018)
  • Author(s): Yamamoto C, Ogawa H, Fukuda T, Igarashi A, Okumura H, Uchida N, Hidaka M, Nakamae H, Matsuoka K, Eto T, Ichinohe T, Atsuta Y, Kanda Y.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 24 Issue: 4 Pages: 708-716
  • DOI: 10.1016/j.bbmt.2017.10.043
  • Peer Reviewed
• [Journal Article] Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15). (2018)
  • Author(s): Harada K, Doki N, Aoki J, Mori J, Machida S, Masuko M, Uchida N, Najima Y, Fukuda T, Kanamori H, Ogawa H, Ota S, Ogawa K, Takahashi S, Kasai M, Maeda A, Nagafuji K, Kawakita T, Ichinohe T, Atsuta Y.
  • Journal Title: Hematologica Volume: 103(2) Issue: 2 Pages: e69-e72
  • DOI: 10.3324/haematol.2017.179804
  • Peer Reviewed / Open Access
• [Journal Article] Impaired skeletal muscle oxygenation following allogeneic hematopoietic stemcell transplantation is associated with exercise capacity (2018)
  • Author(s): Tatsushi Wakasugi, Shinichiro Morishita, Katsuji Kaida, Yusuke Itani, Norihiko Kodama, Kazuhiro Ikegame Hiroyasu Ogawa, Kazuhisa Domen
  • Journal Title: Supportive Care in Cancer Volume: 26 Issue: 7 Pages: 2149-2160
  • DOI: 10.1007/s00520-017-4036-6
  • Peer Reviewed
• [Journal Article] Changes in Borg scale for resistance training and test of exercise tolerance in patients undergoing allogeneic hematopoietic stem cell transplantation. (2018)
  • Author(s): Morishita S, Wakasugi T, Tanaka T, Harada T, Kaida K, Ikegame K, Ogawa H, Domen K.
  • Journal Title: Support Care Cancer. Volume: 26 Issue: 9 Pages: 3217-3223
  • DOI: 10.1007/s00520-018-4168-3
  • Peer Reviewed
• [Journal Article] Effect of cytogenetic risk status on outcomes for patients with acute myeloid leukemia undergoing various types of allogeneic hematopoietic cell transplantation: an analysis of 7812 patients. (2018)
  • Author(s): Yanada M, Mori J, Aoki J, Harada K, Mizuno S, Uchida N, Kurosawa S, Toya T, Kanamori H, Ozawa Y, Ogawa H, Henzan H, Iwato K, Sakura T, Ota S, Fukuda T, Ichinohe T, Atsuta Y, Yano S.
  • Journal Title: Leuk Lymphoma Volume: 59 Issue: 3 Pages: 601-609
  • DOI: 10.1080/10428194.2017.1357173
  • Peer Reviewed
• [Journal Article] Relationship of physical activity with physical function and health-related quality of life in patients having undergone allogeneic haematopoietic stem-cell transplantation (2017)
  • Author(s): Morishita S et al.
  • Journal Title: Eur J Cancer Care (Engl) Volume: [Epub ahead of print] Issue: 4 Pages: e12669-e12669
  • DOI: 10.1111/ecc.12669
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effective desensitization of donor-specific HLA antibodies using platelet transfusion bearing targeted HLA in a case of HLA-mismatched allogeneic stem cell transplantation (2017)
  • Author(s): Yamashita T, Ogawa H, et al.
  • Journal Title: Bone Marrow Transplantation Volume: 印刷中 Issue: 5 Pages: 794-796
  • DOI: 10.1038/bmt.2017.10
  • Peer Reviewed
• [Journal Article] Spousal hematopoietic stem cell transplantation. (2017)
  • Author(s): Ikegame K, Okada M et al.,
  • Journal Title: International Jounal of Hematol. Volume: 105 Issue: 5 Pages: 645-657
  • DOI: 10.1007/s12185-016-2168-y
  • Peer Reviewed
• [Presentation] homeostatic proliferationを介して、steroid抵抗性に増殖する骨髄ドナーT細胞は、GVHとGVLの解離を起こす (2019)
  • Author(s): 井上 貴之、池亀 和博、玉置 広哉、小川 啓恭
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] AYA世代におけるHLA半合致移植―移植の成績と問題点 (2019)
  • Author(s): 大杉夕子、海田 勝仁、池亀 和博、川口真理子、吉原 哲、福永 景子、吉原 亨子、井上 貴之、玉置 広哉、岡田 昌也、藤盛 好啓、小川 啓恭
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] 当科における同種造血幹細胞移植後の2次性悪性腫瘍 (2019)
  • Author(s): 岡田 昌也、福永 景子、井上 貴之、海田 勝仁、吉原 亨子、吉原 哲、池亀 和博、玉置 広哉、大杉夕子、藤盛 好啓、小川 啓恭
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] 日本人同種造血幹細胞移植患者における抗ヒト胸腺細胞ウサギ免疫グロブリンの血中動態とその変動要因の検討 (2019)
  • Author(s): 松元 加奈、海田 勝仁、福永 景子、池亀 和博、小川 啓恭、森田 邦彦
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] Effect of allegeneic stem cell transplantation for patients with minimally differentiated AML (2018)
  • Author(s): Yamasaki S, Aoki J, Mori J, Harada K, Sawa M, Uchida N, Ohashi K, Fukuda T, Koh S, Kanamori H, Ogawa H, Okumura H, Ichinohe T, Kanda Y, Tanaka J, Atsuta Y, Yanada M, Yano S
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Prognostic models after stem cell transplantation using deep learning and general additive model, (2018)
  • Author(s): Ikegame K, Kaida K, Fukunaga K, Inoue T, Osugi Y, Tamaki H, Okada M, Yoshihara S, Fujimori Y, Ogawa H, Tsujitani M
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Alloegeneic hematopoietic stem cell transplantation in patients with B-ALL with t(4; 11)(q21; q23) (2018)
  • Author(s): Aoki J, Fujisawa S, Mizuta S, Ozawa Y, Ohashi K, Ota S, Ogawa H, Fukuda T, Uchida N, Tanaka J, Atsuta Y, Kako S,
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] The efficacy of mesenchymal stem cells for the treatment od steroid-refractory acute GVHD (2018)
  • Author(s): Fukunaga K, Ikegame K, Kaida K, Inoue T, Yoshihara S, Yoshihara K, Osugi Y, Tamaki H, Okada M, Ogawa H, Fijimori Y
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] A case of hemophagocytic syndrome with a Guilain-Barre syndrome-like symptom after delivery (2018)
  • Author(s): Tokugawa T, Sawada A, Okada M, Higasa S, Ikegame K, Ogawa H, Fujimori Y,
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Duration of remission with autologous hematopietic recovery after CBT in leukemia (2018)
  • Author(s): Osugi Y, Tamaki H, Okada M, Inoue T, Fukunaga K, Yoshihara K, Kaida K, Yoshihara S, Ikegame K, Fujimori Y, Ogawa H
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 非寛解白血病に対するハプロミニ移植におけるWT1測定の意義:単施設解析 (2018)
  • Author(s): 玉置 広哉、池亀 和博、海田 勝仁、丸山 聡、眞弓あずさ、井上 貴之、寺本 昌弘、吉原 哲、岡田 昌也、小川 啓恭
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] アデノウイルス11型抗体による出血性膀胱炎の発症予測とシドフォビル予防投与の有用性に関する検討 (2018)
  • Author(s): 福永 景子、池亀 和博、海田 勝仁、丸山 聡、寺本 昌弘、眞弓 あずさ、井上 貴之、岡田 昌也、玉置 広哉、小川 啓恭
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] 血液腫瘍患者の下肢筋力には血清ヘモグロビン値と骨格筋における酸素抽出能が関与している (2018)
  • Author(s): 若杉 樹史、森下 慎一郎、海田 勝仁、池亀 和博、田中 隆史、曽田 幸一郎、原田 鉄也、井谷 祐介、梅地 篤史、児玉 典彦、小川 啓 恭、道免 和久
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] HLA不適合骨髄非破壊的移植における低線量TBIの臨床的意義 (2018)
  • Author(s): 藤原 慎一郎、諫田 淳也、多々良 礼音、小川 啓恭、福田 隆浩、奥村 廣和、大橋 一輝、岩戸 康浩、上田 恭典、内田 直之、鬼塚 真 仁、熱田 由子、神田 善伸
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] 非寛解白血病に対するハプロミニ移植におけるWT1測定の意義：単施設解析. (2018)
  • Author(s): 玉置 広哉、池亀 和博、海田 勝仁、丸山 聡、眞弓あずさ、井上 貴之、寺本 昌弘、吉原 哲、岡田 昌也、小川 啓恭
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] 血液腫瘍患者の下肢筋力には血清ヘモグロビン値と骨格筋における酸素抽出能が関与している (2018)
  • Author(s): 若杉 樹史、森下 慎一郎、海田 勝仁、池亀 和博、田中 隆史、曽田 幸一郎、原田 鉄也、井谷 祐介、梅地 篤史、児玉 典彦、小川 啓恭、道免 和久
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] HLA不適合骨髄非破壊的移植における低線量TBIの臨床的意義. (2018)
  • Author(s): 藤原 慎一郎、諫田 淳也、多々良 礼音、小川 啓恭、福田 隆浩、奥村 廣和、大橋 一輝、岩戸 康浩、上田 恭典、内田 直之、鬼塚 真仁、熱田 由子、神田 善伸
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] HLA半合致移植における抗ヒト胸腺細胞ウサギ免疫グロブリン製剤の血中濃度モニタリングとGVHD重症度の関係性 (2017)
  • Author(s): 丸山 聡、小川啓恭ら
  • Organizer: 第39回日本造血細胞移植学会総会
  • Place of Presentation: 島根県民会館 島根県 松江
  • Year and Date: 2017-03-02
• [Presentation] 同種造血幹細胞移植後に神経症状を呈し経過中に増悪した一例、トキソプラズマ症と中枢神経系EBV関連移植後リンパ増殖性疾患 (2017)
  • Author(s): 眞弓あずさ、小川啓恭ら
  • Organizer: 第39回日本造血細胞移植学会総会
  • Place of Presentation: くにびきメッセ 島根県 松江
  • Year and Date: 2017-03-02
• [Presentation] 急性GVHDによる重度肝機能障害に対し、造血幹細胞と同一ドナーから生体肝移植を施行した急性骨髄性白血病の1例 (2017)
  • Author(s): 寺本昌弘、小川啓恭ら
  • Organizer: 第39回日本造血細胞移植学会総会
  • Place of Presentation: くにびきメッセ 島根県 松江
  • Year and Date: 2017-03-02
• [Presentation] 急性白血病に対する減量前治療を用いた臍帯血移植におけるGVHD予防法の比較研究 (2017)
  • Author(s): 寺倉精太郎、鍬塚 八千代、山崎 聡、和気 敦、諫田 淳也、稲本 賢弘、水田 秀一、山口 拓洋、内田 直之、香西 康司、青墳 信之、小川 啓恭、金森 平和、西脇 嘉一、宮腰 重三郎、鬼塚 真仁、天野 逸人、福田 隆浩、一戸 辰夫、熱田 由子
  • Organizer: 第79回日本血液学会学術集会