Attempts to answer the crucial qeustion if the anti-tumor cellular immune system can eradicate leukemia stem cells-an analysis using humanized mouse system-

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591245
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Ehime University
• Principal Investigator: FUJIWARA Hiroshi 愛媛大学, 医学部附属病院, 講師 (20398291)
• Project Period (FY): 2009 – 2011
• Keywords: 細胞傷害性Tリンパ球(CTL) / がん抗原特異的T細胞受容体(TCR)遺伝子 / 遺伝子改変Tリンパ球 / 白血病性幹細胞 / 細胞免疫療法 / 同種造血幹細胞移植術

Research Abstract

Aiming at cure of leukemia, we are developing a novel cellular immunotherapy using genetically modified T lymphocytes to express leukemia antigen specific T-cell receptor(TCR) which can recognize leukemia stem cells(LSCs). In this study, we have demonstrated the clinical feasibility of two therapeutic options targeting Wilms' tumor gene product 1(WT1) and Aurora kinase A(AURKA), and the usefulness of a novel TCR gene expression vector(siTCR vector) which simultaneously encodes silencers for endogenous TCRs. Currently, this on-going study using a xenografted NOG mouse model are accumulating positive lines of evidence that adoptively transferred LSC-specific CTLs can prohibit leukemia progression in vivo.

Research Products

• [Journal Article] Aurora kinase A-specific T-cell receptor gene transfer redirects T-lymphocytes to display effective anti-leukemia reactivity (2012)
  • Author(s): Nagai K, Ochi T, Fujiwara H, An J, Shirakata T, Mineno J, Kuzushima K, Shiku H, Melenhorst J, Gostic E, Price D. A., Ishii E, Yasukawa M
  • Journal Title: Blood. Volume: 119(2) Pages: 368-76
  • Peer Reviewed
• [Journal Article] Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked anti-leukemia reactivity and safety (2011)
  • Author(s): Ochi T, Fujiwara H, Okamoto S, An J, Nagai K, Shirakata T, Mineno J, Kuzushima K, Shiku H, Yasukawa M
  • Journal Title: Blood. Volume: 118(6) Pages: 1495-503
  • Peer Reviewed
• [Journal Article] Gemcitabine enhances Wilms' tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response (2011)
  • Author(s): Takahara A, Koido S, Ito M, Nagasaki E, Sagawa Y, Iwamoto T, Komita H, Ochi T, Fujiwara H, Yasukawa M, Mineno J, Shiku H, Nishida S, Sugiyama H, Tajiri H, Homma S
  • Journal Title: Cancer Immunol Immunother. Volume: 60(9) Pages: 1289-97
  • Peer Reviewed
• [Journal Article] Feasibility of gene-immunotherapy using WT1-specific T-cell receptor gene transfer for infant acute lymphoblastic leukemia with MLL gene rearrangement (2011)
  • Author(s): Nagai K, Fujiwara H, Ochi T, Okamoto S, Mineno J, Shiku H, Koh K, Sugita K, Ishii E, Yasukawa M
  • Journal Title: Blood Cancer Journal Volume: 1 Pages: e10
  • DOI: doi:10.1038/bcj
  • Peer Reviewed
• [Journal Article] Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis (2011)
  • Author(s): An J, Fujiwara H, Suemori K, Niiya T, Azuma T, Tanimoto K, Ochi T, Akatsuka Y, Mineno J, Ozawa H, Ishikawa F, Kuzushima K, Yasukawa M
  • Journal Title: Int J Hematol. Volume: 93(2) Pages: 176-185
  • Peer Reviewed
• [Journal Article] 遺伝子改変T細胞を用いた悪性腫瘍に対する細胞免疫療法 (2011)
  • Author(s): 藤原弘
  • Journal Title: 臨床血液 Volume: 52(5) Pages: 243-255
• [Journal Article] Requisite considerations for successful adoptive immunotherapy with engineered T-lymphocytes using tumor antigen-specific T-cell receptor gene transfer (2011)
  • Author(s): Ochi T, Fujiwara H, Yasukawa M
  • Journal Title: Expert Opin Biol Ther. Volume: 11(6) Pages: 699-713
  • Peer Reviewed
• [Journal Article] Application of adoptive T-cell therapy using tumor antigen-specific T-cell receptor gene transfer for the treatment of human leukemia (2010)
  • Author(s): Ochi T, Fujiwara H, Yasukawa M
  • Journal Title: J Biomed Biotechnol. Pages: 521248
  • Peer Reviewed
• [Journal Article] Allo-HLA reactivity of leukemia-specific cytotoxic T lymphocytes (2010)
  • Author(s): Yasukawa M, Nagai K, Fujiwara H, Ochi T, Akatsuka Y, Mineno J and Shiku H
  • Journal Title: Blood Volume: (e-Letters)
  • Peer Reviewed
• [Journal Article] Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice (2010)
  • Author(s): Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F
  • Journal Title: Proc Natl Acad Sci USA. Volume: 107(29) Pages: 13022-7
  • Peer Reviewed
• [Journal Article] Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR (2009)
  • Author(s): Okamoto S, Mineno J, Ikeda H, Fujiwara H, Yasukawa M, Shiku H, Kato I
  • Journal Title: Cancer Res. Volume: 69(23) Pages: 9003-11
  • Peer Reviewed
• [Journal Article] Aurora-A kinase : a novel target both for cellular immunotherapy and molecular target therapy against human leukemia (2009)
  • Author(s): Ochi T, Fujiwara H, Yasukawa M
  • Journal Title: Expert Opin Ther Targets. Volume: 13(12) Pages: 1399-410
  • Peer Reviewed
• [Journal Article] 造血器腫瘍関連抗原の同定と臨床応用 (2009)
  • Author(s): 藤原弘
  • Journal Title: 臨床血液 Volume: 50(5) Pages: 340-351
• [Presentation] 抗白血病性T細胞ネットワークを輸注する次世代型遺伝子免疫療法の開発研究 (2012)
  • Author(s): 藤原弘, 他
  • Organizer: 第34回日本造血細胞移植学会総会(ワークショップ)
  • Place of Presentation: 大阪市
  • Year and Date: 2012-02-24
• [Presentation] Human telomerase reverse transcriptase-specific T-cell receptor gene transfer redirects T-lymphocytes to exert effective antitumor reactivity against adult T-cell leukemia (2011)
  • Author(s): Yukihiro Miyazaki et al
  • Organizer: 第53回アメリカ血液学会総会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-12
• [Presentation] Redirected CD4+ T cells using WT1-specific T-cell receptor gene transfe can supply multifactorial help to enhance the anti-leukemia reactivity mediated by similarly redirected CD8+ T cells using the identical gene transfer (2011)
  • Author(s): Toshiki Ochi et al
  • Organizer: 第53回アメリカ血液学会総会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-12
• [Presentation] Forced expression of CC chemokine receptor 2 enhances anti-cancer reactivity mediated by T lymphocytes beforehand redirected toward WT1 inside the tumor microenvironment (2011)
  • Author(s): Hiroaki Aasai et al
  • Organizer: 第53回アメリカ血液学会総会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-10
• [Presentation] Detailed assessment of anti-leukemia effect and safety of redirected T cells using WT1-siTCR vector (2011)
  • Author(s): Hiroshi Fujiwara et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 2011-11-14
• [Presentation] Anti-leukemia functionality mediated by redirected T cells using LAA-specific TCR ; aiming at the persistent control of leukemia stem cells (2011)
  • Author(s): Hiroshi Fujiwara
  • Organizer: Invited lecture at National Heart, Lung and Blood Institute/NIH(招聘講演)
  • Place of Presentation: Bethesda, MA, USA
  • Year and Date: 2011-09-21
• [Presentation] Dual engineering of human CD8^+ T-cells with WT1-specific TCR gene and chemokine receptor gene transfer confers functionally strengthened anti-cancer reactivity (2011)
  • Author(s): Hiroshi Fujiwara et al
  • Organizer: 5^<th> International Conference on WT1 in Human Neoplasia(招聘講演)
  • Place of Presentation: Turin, Italy
  • Year and Date: 2011-04-15
• [Presentation] Engineered T-lymphocytes using a novel anti-leukemia antigen, aurora-Akinase-specific T-cell receptor gene transfer successfully displayed anti-leukemia reactivity (2011)
  • Author(s): Hiroshi Fujiwara et al
  • Organizer: 37^<th> Annual Congress of European Group for Blood and Barrow Transplantation(EBMT総会)(Van Bekkum Award受賞講演)
  • Place of Presentation: Paris France
  • Year and Date: 2011-04-03
• [Presentation] Augmented expression of WT1-specific TCR and inhibition of mispaired TCR formation in TCR-gene modified T cells can concomitantly be achieved using a novel retroviral vector with silencers for endogenous TCRs (2010)
  • Author(s): Toshiki Ochi et al
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-12-07
• [Presentation] Dual engineering of human CD8^+ T cells with WT1-specific TCR gene and chemokine receptor gene transfer confers functionally strengthened anti-cancer reactivity (2010)
  • Author(s): Kozo Nagai et al
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-12-06
• [Presentation] Engineered human T cells with a novel Aurora-A kinase-specific T-cell receptor gene transfer confers anti-leukemia reactivity (2010)
  • Author(s): Yukihiro Miyazaki et al
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-12-06
• [Presentation] Gene-engineered T-cell therapy against malignancies (2010)
  • Author(s): Hiroshi Fujiwara
  • Organizer: 第72回血液学会学術集会・シンポジウム1 Cancer immunotherapy : Current status and future prospects(招聘講演)
  • Place of Presentation: 横浜市
  • Year and Date: 2010-10-24
• [Presentation] Our current attempts to develop a novel gene-immunotherapy against human leukemia (2010)
  • Author(s): Hiroshi Fujiwara
  • Organizer: Invited lecture at National Heart, Lung and Blood Institute/NIH(招聘講演)
  • Place of Presentation: Bethesda, MA, USA
  • Year and Date: 2010-08-02
• [Presentation] Genetically engineered T-cell therapy for cancer (2010)
  • Author(s): Hiroshi Fujiwara
  • Organizer: 第16回日本遺伝子治療学会(JSGT)年次学術集会・Joint Symposium with the Society of Immunotherapy for Hematological Malignancies Cancer Immunotherapy & Gene Therapy(招聘講演)
  • Place of Presentation: 宇都宮市
  • Year and Date: 2010-07-03
• [Presentation] Development of gene-immunotherapy against human leukemia with engineered T-cells using WT-1-specific T-cell receptor gene transfer (2010)
  • Author(s): Hiroshi Fujiwara et al
  • Organizer: 36^<th> EBMT総会
  • Place of Presentation: Vienna Austria
  • Year and Date: 2010-03-23
• [Presentation] Development of a novel anti-leukemia immunogenetherapy using Aurora-A kinase-specific T-cell reseptor genes transfer (2009)
  • Author(s): Kozo Nagai et al
  • Organizer: 第51回アメリカ血液学会総会
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2009-12-07
• [Presentation] Development of novel stem cell transplantation and gene-immuno-therapy using WT1-specific T-cell receptor gene (2009)
  • Author(s): Toshiki Ochi et al
  • Organizer: 第51回アメリカ血液学会総会
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2009-12-07
• [Presentation] Development of immune-gene therapy using Aurora-A kinase specific T-cell receptor gene (2009)
  • Author(s): Hiroshi Fujiwara et al
  • Organizer: 第68回日本癌学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-10-03
• [Remarks] 愛媛大学大学院生体統御内科学分野ホームページ
  • URL: http://www.m.ehime-u.ac.jp/school/int.med1/
• [Patent(Industrial Property Rights)] T細胞レセプター及び該レセプターをコードする核酸 (2010)
  • Inventor(s): 安川正貴、藤原弘、越智俊元、峰野純一、加藤郁之進
  • Industrial Property Rights Holder: 国立大学法人愛媛大学、タカラバイオ(株)
  • Industrial Property Number: 国際公開番号WO2010/114129A1
  • Acquisition Date: 2010-10-07
  • Overseas