2016 Fiscal Year Annual Research Report
Development of Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes (CTL) therapy for EBV-LPD after hematopoietic stem cell transplantation
| Project/Area Number |
26461580
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| Research Institution | Nagoya University |
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Principal Investigator |
高橋 義行 名古屋大学, 医学系研究科, 教授 (40432273)
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| Co-Investigator(Kenkyū-buntansha) |
小島 勢二 名古屋大学, 医学系研究科, 名誉教授 (20313992)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Keywords | 小児血液学 / 造血幹細胞移植 / EBウイルス / CTL |
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| Outline of Annual Research Achievements |
１）造血幹細胞移植後にEBV再活性化およびウイルス特異的CTL体内動態の観察：90例以上の移植後患者末梢血液中EBV-DNA定量を行い、ATG血中濃度をELISA法により測定し、EBV再活性化との関連を検討した。またEBV再活性の新規症例においてはRituxan投与前後にフローサイトメトリー法による末梢血中のリンパ球サブセットの解析を行い、CD20陰性CD19陽性細胞の有無を同定した。Rituxan投与後にEBV-DNA増加症例においては、EBERに対するプローブを用いたフローサイトメトリーFISH法を用いてEBV感染細胞の同定、EBV特異的CTLテトマラー染色によりEBV特異的CTLのモニタリングが可能となった。
２）EBV特異的CTL存在下で発症するEB-LPDにおけるエスケープメカニズムの検討：造血幹細胞移植後に体内にEBV特異的CTLが存在しながら免疫抑制剤を中止してもEB-LPDが縮小しない症例を経験し、LMP2,EBNA3A,EBNA3BといったEBV抗原発現について発現が消失していることを確認した。
３）HLA-A0201/0206,A2402以外のHLA拘束性EBV抗原ペプチドによる対象HLAの拡大：現在当院で行っている「同種造血幹細胞移植後において生じるEBV関連リンパ球増殖症に対するEBV抗原特異的CTLを用いた治療の安全性に関する臨床第I相試験」で用いられているEBV抗原ペプチドはHLA-A0201/0206,A2402拘束性であるが、HLA-A11拘束性ペプチドを合成し、新たにEBV特異的CTLとして培養可能であった。
４）第3者由来末梢血からEBV特異的CTLを培養し、凍結保存しておき、移植後リツキシマブ抵抗性EB-LPDに投与する第Ｉ相試験が再生医療新法に基づいて承認された。
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[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.
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Journal Title
Br J Haematol.
Volume: 176
Pages: 248-257
DOI
Peer Reviewed
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[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, Childs RW
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Journal Title
Cancer Res.
Volume: 76
Pages: 2177-2185
DOI
Peer Reviewed
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[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
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Journal Title
Haematologica
Volume: 101
Pages: 644-652
DOI
Peer Reviewed
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[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.
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Journal Title
Int J Hematol.
Volume: 104
Pages: 130-133
DOI
Peer Reviewed
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[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.
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Journal Title
Int J Hematol.
Volume: 104
Pages: 266-267
DOI
Peer Reviewed
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[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.
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Journal Title
J Clin Oncol.
Volume: 34
Pages: 3451-3459
DOI
Peer Reviewed
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[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.
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Journal Title
Biol Blood Marrow Transplant.
Volume: 22
Pages: 1836-1843
DOI
Peer Reviewed
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[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.
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Journal Title
J Allergy Clin Immunol.
Volume: 138
Pages: 1471-1473
DOI
Peer Reviewed
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[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.
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Journal Title
Biol Blood Marrow Transplant.
Volume: 22
Pages: 2226-2234
DOI
Peer Reviewed
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[Presentation] PiggyBac transposon, a non-viral gene transfer system, mediated T cells expressing CD19 chimeric antigen receptor for a "first in human" clinical trial2017
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
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[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
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