Development of Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes (CTL) therapy for EBV-LPD after hematopoietic stem cell transplantation

• Project/Area Number: 26461580
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• 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): 小島 勢二 名古屋大学, 医学系研究科, 名誉教授 (20313992)
• Co-Investigator(Renkei-kenkyūsha): KIMURA Hiroshi 名古屋大学, 大学院医学系研究科, 教授 (30303621) ; MIZUNO Masaaki 名古屋大学, 医学部附属病院, 病院教授 (70283439)
• Research Collaborator: LEEN Ann 米国ベイラー医科大学, Pediatrics-Hem-Onc Cell & Gene, 助教 ; SAJI Hiroo HLA研究所, 所長
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ＥＢウイルス / 造血幹細胞移植 / ＣＴＬ / 小児血液学 / EBウイルス / CTL / ウイルス / 造血細胞移植 / 細胞療法

Outline of Final Research Achievements

We analyzed the relation of EBV reactivation and Anti-thymocyte globulin (ATG) blood concentration in 90 cases and revealed that EBV reactivation was significantly more in high ATG concentration group. We could successfully developed EBV specific CTLs from 3rd party donors using not only HLA A2402/A0201 peptides but also HLA-A11 restricted peptides. We started the phase 1 clinical trial of EBV specific CTL therapy from the 3rd party donors.

Research Products

• [Journal Article] Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia. (2017)
  • Author(s): Sekiya Y, Xu Y, Muramatsu H, Okuno Y, Narita A, Suzuki K, Wang X, Kawashima N, Sakaguchi H, Yoshida N, Hama A, Takahashi Y, Kato K, Kojima S.
  • Journal Title: Br J Haematol. Volume: 176 Issue: 2 Pages: 248-257
  • DOI: 10.1111/bjh.14420
  • Peer Reviewed
• [Journal Article] Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer (2016)
  • Author(s): Cherkasova E., Scrivani C., Doh S., Weisman Q., Takahashi Y., Harashima N., Yokoyama H., Srinivasan R., Linehan WM., Lerman MI., and Childs RW.
  • Journal Title: Cancer Research Volume: 76 (8) Issue: 8 Pages: 2177-2185
  • DOI: 10.1158/0008-5472.can-15-3139
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia. (2016)
  • Author(s): Arai Y, Kondo T, Yamazaki H, Takenaka K, Sugita J, Kobayashi T, Ozawa Y, Uchida N, Iwato K, Kobayashi N, Takahashi Y, Ishiyama K, Fukuda T, Ichinohe T, Atsuta Y, Mori T, Teshima T, Japan Society for Hematopoietic Cell Transplantation
  • Journal Title: Haematologica Volume: 101 Issue: 5 Pages: 644-652
  • DOI: 10.3324/haematol.2015.139469
  • Peer Reviewed
• [Journal Article] Application of extensively targeted next-generation sequencing for the diagnosis of primary immunodeficiencies. (2016)
  • Author(s): Kojima D, Wang X, Muramatsu H, Okuno Y, Nishio N, Hama A, Tsuge I, Takahashi Y, Kojima S.
  • Journal Title: J Allergy Clin Immunol. Volume: 138 Issue: 1 Pages: 303-305
  • DOI: 10.1016/j.jaci.2016.01.012
  • Peer Reviewed
• [Journal Article] Immunosuppressive therapy for patients with Down syndrome and idiopathic aplastic anemia. (2016)
  • Author(s): Suzuki K, Muramatsu H, Okuno Y, Narita A, Hama A, Takahashi Y, Yoshida M, Horikoshi Y, Watanabe K, Kudo K, Kojima S.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 1 Pages: 130-133
  • DOI: 10.1007/s12185-016-1997-z
  • Peer Reviewed
• [Journal Article] JAK2, MPL, and CALR mutations in children with essential thrombocythemia. (2016)
  • Author(s): Sekiya Y, Okuno Y, Muramatsu H, Ismael O, Kawashima N, Narita A, Wang X, Xu Y, Hama A, Fujisaki H, Imamura T, Hasegawa D, Kosaka Y, Sunami S, Ohtsuka Y, Ohga S, Takahashi Y, Kojima S, Shimada A.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 2 Pages: 266-267
  • DOI: 10.1007/s12185-016-2022-2
  • Peer Reviewed
• [Journal Article] Kampo patterns and radiology in children receiving choreito for hemorrhagic cystitis after hematopoietic stem cell transplantation. (2016)
  • Author(s): Kawashima N, Sekiya Y, Narita A, Kamei M, Muramatsu H, Nishio N, Hama A, Ito Y, Takahashi Y, Kojima S.
  • Journal Title: 3451 Volume: 3 Issue: 2 Pages: 136-144
  • DOI: 10.1002/tkm2.1053
  • Peer Reviewed
• [Journal Article] MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents. (2016)
  • Author(s): Suzuki K, Okuno Y, Kawashima N, Muramatsu H, Okuno T, Wang X, Kataoka S, Sekiya Y, Hamada M, Murakami N, Kojima D, Narita K, Narita A, Sakaguchi H, Sakaguchi K, Yoshida N, Nishio N, Hama A, Takahashi Y, Kudo K, Kato K, Kojima S.
  • Journal Title: J Clin Oncol. Volume: 34 Issue: 28 Pages: 3451-3459
  • DOI: 10.1200/jco.2016.66.5547
  • Peer Reviewed
• [Journal Article] A Comparison of Outcomes for Cord Blood Transplantation and Unrelated Bone Marrow Transplantation in Adult Aplastic Anemia. (2016)
  • Author(s): Kuwatsuka Y, Kanda J, Yamazaki H, Mori T, Miyamura K, Kako S, Uchida N, Ohashi K, Ozawa Y, Takahashi Y, Kato C, Iwato K, Ishiyama K, Kobayashi H, Eto T, Kahata K, Kato J, Miyamoto T, Kato K, Mori S, Atsuta Y, Kimura F, Kanda Y, Japan Society for Hematopoietic Cell Transplantation.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Pages: 1836-1843
  • Peer Reviewed
• [Journal Article] Successful T-cell reconstitution after unrelated cord blood transplantation in a patient with complete DiGeorge syndrome. (2016)
  • Author(s): Kojima D, Muramatsu H, Okuno Y, Kataoka S, Murakami N, Tanahashi Y, Suzuki K, Kato T, Sekiya Y, Kawashima N, Narita A, Nishio N, Hama A, Imai K, Nonoyama S, Takahashi Y, Kojima S.
  • Journal Title: J Allergy Clin Immunol. Volume: 138 Issue: 5 Pages: 1471-1473
  • DOI: 10.1016/j.jaci.2016.04.048
  • NAID: 120005981223
  • Peer Reviewed
• [Journal Article] Comparison of Donor Sources in Hematopoietic Stem Cell Transplantation for Childhood Acute Leukemia: A Nationwide Retrospective Study. (2016)
  • Author(s): Sakaguchi H, Watanabe N, Matsumoto K, Yabe H, Kato S, Ogawa A, Inagaki J, Goto H, Koh K, Yoshida N, Kato K, Cho Y, Kosaka Y, Takahashi Y, Inoue M, Kato K, Atsuta Y, Miyamura K, Donor/Source Working Group of Japan Society of Hematopoietic Cell Transplantation.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Issue: 12 Pages: 2226-2234
  • DOI: 10.1016/j.bbmt.2016.09.020
  • Peer Reviewed
• [Journal Article] Virological analysis of inherited chromosomally integrated human herpesvirus-6 in three hematopoietic stem cell transplant patients. (2015)
  • Author(s): Miura H, Kawamura Y, Kudo K, Ihira M, Ohye T, Kurahashi H, Kawashima N, Miyamura K, Yoshida N, Kato K, Takahashi Y, Kojima S, Yoshikawa T.
  • Journal Title: Transpl Infect Dis. Volume: 17 Issue: 5 Pages: 728-731
  • DOI: 10.1111/tid.12419
  • Peer Reviewed / Open Access
• [Journal Article] Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases (2015)
  • Author(s): Kawashima N, Muramatsu H, Okuno Y, Torii Y, Kawada J, Narita A, Nakamura S, Takahashi Y, Ito Y, Kojima S
  • Journal Title: Journal of infection and chemotherapy Volume: 21 Issue: 12 Pages: 857-63
  • DOI: 10.1016/j.jiac.2015.08.018
  • Peer Reviewed / Open Access
• [Journal Article] Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. (2015)
  • Author(s): Kawashima N, Ito Y, Sekiya Y, Narita A, Okuno Y, Muramatsu H, Irie M, Hama A, Takahashi Y, Kojima S.
  • Journal Title: Biol Blood Marrow Transplant Volume: 21 Issue: 2 Pages: 319-325
  • DOI: 10.1016/j.bbmt.2014.10.018
  • Peer Reviewed
• [Journal Article] Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia. (2014)
  • Author(s): Kobayashi R, Yabe H, Kikuchi A, Kudo K, Yoshida N, Watanabe K, Muramatsu H, Takahashi Y, Inoue M, Koh K, Inagaki J, Okamoto Y, Sakamaki H, Kawa K, Kato K, Suzuki R, Kojima S
  • Journal Title: Biol Blood Marrow Transplant Volume: 20 Issue: 8 Pages: 1145-1149
  • DOI: 10.1016/j.bbmt.2014.04.006
  • Peer Reviewed
• [Presentation] PiggyBac transposon, a non-viral gene transfer system, mediated T cells expressing CD19 chimeric antigen receptor for a "first in human" clinical trial (2017)
  • Author(s): Yoshiyuki Takahashi, Nobuhiro Nishio, Motoharu Hamada, Miyuki Takana, Daisuke Morita, Nozomu Kawashima, Yusuke Okuno, Atsushi Narita, Asahito Hama, Hideki Muramatsu, Gianpietro Dotti, Seiji Kojima, Yozo Nakazawa
  • Organizer: EBMT
  • Place of Presentation: Marseille, France
  • Year and Date: 2017-03-27
  • Int'l Joint Research
• [Presentation] Phase I bridging study of ch14.18/CHO long-term infusion in recurrent or refractory neuroblastoma patients in Japan. (2016)
  • Author(s): Atsushi Narita, Yoshiyuki Takahashi, Nikolai Slebert, Nobuhiro Nishio, Xinan Wang, Yinyan Xu, Yusuke Okuno, Daiei Kojima, Kyogo Suzuki, Seiji Kojima, et al.
  • Organizer: 2016ASCO Annual Meeting.
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-06-06
  • Int'l Joint Research
• [Presentation] Excellent outcome of Hematopoietic stem cell transplantation in children with acquired aplastic anemia from alternative donor. (2016)
  • Author(s): Yoshiyuki Takahashi.
  • Organizer: 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation.
  • Place of Presentation: Valencia, Spain
  • Year and Date: 2016-04-06
  • Int'l Joint Research
• [Presentation] 小児後天性再生不良性貧血67例に対する同種造血細胞移植 (2016)
  • Author(s): 高橋 義行、小島 大英、村上 典寛、鈴木 喬悟、関屋 由子、川島 希、亀井 美智、 西尾 信博、奥野 友介、成田 敦、村松 秀城、濱 麻人、小島 勢二
  • Organizer: 第38回日本造血細胞移植学会総会
  • Place of Presentation: 愛知県名古屋市（名古屋国際会議場）
  • Year and Date: 2016-03-03
  • Int'l Joint Research
• [Presentation] Haploidentical Hematopoietic Stem Cell Transplantation in Children andAdolescents with Acquired Severe Aplastic Anemia. (2015)
  • Author(s): Yoshiyuki Takahashi, Ho Joon Im, Kyung Nam Koh, Chengjuan Luo, Jing Chen, Hideki Muramatsu, Asahito Hama, Jong Jin Seo and Seiji Kojima
  • Organizer: The 6th JSH International Symposium 2015.
  • Place of Presentation: 長野県北佐久郡軽井沢町（軽井沢プリンスホテルウェスト）
  • Year and Date: 2015-05-22
  • Int'l Joint Research
• [Presentation] 長期保存されたウイルス特異的細胞傷害性T細胞の安定性に関する検討 (2015)
  • Author(s): 西尾 信博、鈴木 哲、鍬塚 八千代、西田 徹也、村田 誠、清井 仁、高橋 義行、小島 勢二.
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 兵庫県神戸市、神戸国際会議場
  • Year and Date: 2015-03-06
• [Presentation] Unmanipulated HLA haploidentical bone marrow transplantation combined with PBSC using high dose ATG. (2014)
  • Author(s): 高橋 義行、関屋 由子、川島 希、成田 敦、土居崎 小夜子、奥野 友介、入江 正寛、村松 秀城、濱 麻人、小島 勢二.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪府大阪市、大阪国際会議場
  • Year and Date: 2014-10-31