Novel hematopoietic stem cell transplantation using cancer-specific T-cell receptor gene transfer

• Project/Area Number: 19390265
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Ehime University
• Principal Investigator: YASUKAWA Masaki Ehime University, 大学院・医学系研究科, 教授 (60127917)
• Co-Investigator(Kenkyū-buntansha): 薬師神 芳洋 愛媛大学, 医学部附属病院, 講師 (30294797)
• Co-Investigator(Renkei-kenkyūsha): YAKUSHIJIN Yoshihiro 愛媛大学, 医学部・附属病院, 講師 (30294797)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2007: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: がん免疫療法 / 細胞傷害性T細胞 / T細胞レセプター遺伝子 / 遺伝子治療 / 造血幹細胞移植 / T細胞レセプター / 造血幹細胞 / がん免疫 / 白血病

Research Abstract

革新的造血幹細胞移植療法の開発の目的で、新たな造血器腫瘍関連抗原の同定と腫瘍特異的細胞傷害性T細胞(CTL)由来T細胞レセプター(TCR)遺伝子導入による免疫遺伝子治療の開発をおこなった。その結果、新たな白血病関連抗原として、CML66とAurora-Aを同定した。また、がん特異的CTL由来TCR遺伝子導入によって、HLA拘束性のがん特異性を獲得することが確認された。さらに、がん特異的TCR遺伝子導入造血幹細胞が、マウス体内でがん特異的成熟T細胞に分化増殖できることを確認しえたことから、今後、GVHDに頼らない新たな自己造血幹細胞移植療法の開発が可能であることが示された。

Research Products

• [Journal Article] The role of zinc finger protein 521/early hematopoietic zinc finger protein in erythroid cell differentiation (2009)
  • Author(s): Matsubara E, Yasukawa M, Yakushijin, Y.,et.al.
  • Journal Title: J.Biol.Chem. 284 Pages: 3480-3487
  • Peer Reviewed
• [Journal Article] Aurora-A kinase : A novel target of cellular immunotherapy for leukemia (2009)
  • Author(s): Ochi, T., Yasukawa, M. Yakushijin, Y., et.al.
  • Journal Title: Blood 113 Pages: 66-74
  • Peer Reviewed
• [Journal Article] HBZ is an immunogenic protein but not a target antigen for HTLV-1-specific cytotoxic T lymphocytes (2009)
  • Author(s): Suemori, K., Yasukawa, M., et al.
  • Journal Title: J Gen Virol (in press)
  • Peer Reviewed
• [Journal Article] Identification of a novel epitope derived from CML66 which is recognized by anti-leukaemia cytotoxic T lymphocytes (2009)
  • Author(s): Suemori, K., Yasukawa, M., et al.
  • Journal Title: Br J Haematol (in press)
  • Peer Reviewed
• [Journal Article] Clinical efficacy of WT1 peptide vaccination in patients with acute myelogenous leukemia and myelodysplastic syndrjome (2009)
  • Author(s): Yasukawa, M., et al.
  • Journal Title: Am J Hematol (in press)
  • Peer Reviewed
• [Journal Article] Clinical significance of co-expression of CD21 and LFA-1 in non-Hodgkin' s B-celllymphoma (2009)
  • Author(s): Tanimoto, K., Yasukawa, M., et al.
  • Journal Title: Int J Hematol (in press)
  • Peer Reviewed
• [Journal Article] The role of zinc finger protein 521/early hematopoietic zinc finger protein in erythroid cell differentiation (2009)
  • Author(s): Matsubara, E., Yasukawa, M., et al.
  • Journal Title: J Biol Chem 284 Pages: 3480-3487
  • Peer Reviewed
• [Journal Article] Aurora-A kinase : A novel target of cellular immunotherapy for leukemia (2009)
  • Author(s): Ochi, T., Yasukawa, M., et al.
  • Journal Title: Blood 113 Pages: 66-74
  • Peer Reviewed
• [Journal Article] Therapeutic effect of accmulaticn of CXCR3-expressing regulatory T cells on liver and intestinal damages in a murine acute GVHD model (2009)
  • Author(s): Hasegawa, H., Yasukawa, M., et al.
  • Journal Title: Gene Ther 15 Pages: 171-182
  • Peer Reviewed
• [Journal Article] Identification of an epitope derived from CML66, a novel tumor-associated antigen broadly expressed in human leukemia, recognized by HLA-A*2402-restricted cytotoxic T lymphocytes (2008)
  • Author(s): Suemori, K., Yasukawa, M. Yakushijin, Y., et.al.
  • Journal Title: Cancer Sci. 99 Pages: 1414-1419
  • Peer Reviewed
• [Journal Article] Allogeneic stem cell transplantation for refractory adult T-cell leukemia using a non-T-cell-depleted HLAincompatible family donor graft, with reference to the grown-up child donor to parent recipient setting : report of a pilot study (2008)
  • Author(s): Fujiwara, H., Yasukawa, M., et.al.
  • Journal Title: Int.J.Hematol 87 Pages: 319-326
  • NAID: 10021256219
  • Peer Reviewed
• [Journal Article] Cooperative role of the membrane-proximal and distal residues of the integrin beta 3 cytoplasmic domain in regulation of talin-mediated alpha IIbbeta 3 activation (2008)
  • Author(s): Hato, T., Yakushijin, Y., Yasukawa, M., et.al.
  • Journal Title: J.Biol. Chem. 283 Pages: 5662-5668
  • Peer Reviewed
• [Journal Article] Therapeutic effect of accumulation of CXCR3-expressing regulatory T cells on liver and intestinal damages in a murine acute GVHD model (2008)
  • Author(s): Hasegawa, H., Yasukawa, M. et.al.
  • Journal Title: Gene Therapy 15 Pages: 171-182
  • Peer Reviewed
• [Journal Article] Identification of an epitope derived from CML66, a novel tumor-associated antigenbroadly expressed in human leukemia, recognized by HLA-A*2402-restxicted cytotoxicT lymphocytes (2008)
  • Author(s): Suemori, K., Yasukawa, M., et al.
  • Journal Title: Cancer Sci 99 Pages: 1414-1419
  • Peer Reviewed
• [Journal Article] Allogeneic stem cell transplantation for refractory adult T-cell leukemia using anon-T-cell-depleted HLA-incompatible family donor graft, with reference to theg rcwn-up child donor to parent recipient setting : report of a pilot study (2008)
  • Author(s): Fujiwara, H., Yasukawa, M., etal.
  • Journal Title: Int J Hematol 87 Pages: 319-326
  • Peer Reviewed
• [Journal Article] Cooperative role of the membrane-proximal and distal residues of the integrin beta3 cytoplasmic domain in regulation of talin-mediated alpha IIbbeta 3 activation (2008)
  • Author(s): Hato, T., Yasukawa, M., et al.
  • Journal Title: J Biol Chem 283 Pages: 5662-5668
  • Peer Reviewed
• [Journal Article] Identification of an epitope derived from CML66, a novel tumor associated antigen broadly expressed in human leukemia, recognized by HLA-A^*2402-restricted cytotoxic T lymphocytes (2008)
  • Author(s): Suemori K, Yasukawa M, et. al.
  • Journal Title: Cancer Sci (In press)
  • Peer Reviewed
• [Journal Article] Cooperative role of the membrane-proximal and distal residues of the integrin beta 3cytoplasmic domain in regulation of talin-・mediated alpha IIbbeta 3 activation (2008)
  • Author(s): Hato T, Yasukawa M, et. al.
  • Journal Title: J.Biol.Chem (In press)
  • Peer Reviewed
• [Journal Article] Therapeutic effect of accumulation of CXCR3-expressing regulatory T cells on liver and intestinal damages in a murine acute GVHD model (2008)
  • Author(s): Hasegawa H, Yasukawa M, et. al.
  • Journal Title: Gene Ther 15 Pages: 171-182
  • Peer Reviewed
• [Journal Article] Wilms tumor gene WT1 peptide-based immunotherapy induced a minimal response in a patient with advanced therapy-resistant multiple myeloma (2007)
  • Author(s): Tsuboi, A., Yasukawa, M., et.al.
  • Journal Title: Int J Hematol 86 Pages: 414-417
  • NAID: 10019533221
  • Peer Reviewed
• [Journal Article] Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis (2007)
  • Author(s): Nagafuji, K., Yasukawa, M., et.al.
  • Journal Title: Haematologica 92 Pages: 978-981
  • Peer Reviewed
• [Journal Article] Nationwide survey of hemophagocytic lymphohistiocytosis in Japan (2007)
  • Author(s): Ishii, E., Yasukawa, M., et.al.
  • Journal Title: Int.J.Hematol 86 Pages: 58-65
  • NAID: 10018515633
  • Peer Reviewed
• [Journal Article] Association of human herpesvirus-6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome (2007)
  • Author(s): Tohyama, M., Yasukawa, M., et.al.
  • Journal Title: Br.J.Dermatol 157 Pages: 934-940
  • Peer Reviewed
• [Journal Article] Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+regulatory T cells in MRL/lpr mice (2007)
  • Author(s): Hasegawa, H., Yasukawa, M., et.al.
  • Journal Title: Arthritis Res. Ther. 9(1)
  • Peer Reviewed
• [Journal Article] A mitotic kinase TOPK enhances cdk1/cyclin B1-dependent phosphorylation of PRC1 and promotes cytokinesis (2007)
  • Author(s): Abe, Y., Yasukawa, M. et.al.
  • Journal Title: J.Mol.Biol. 370 Pages: 231-245
  • Peer Reviewed
• [Journal Article] Absence of chlamydial infection in Japanese patients with ocular adnexal MALT lymphoma (2007)
  • Author(s): Yakushijin, Y., Yasukawa. M. et.al.
  • Journal Title: Int.J.Hematol 85 Pages: 223-230
  • Peer Reviewed
• [Journal Article] The role of Wilms' tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal nocturnal hemoglobinuria clone (2007)
  • Author(s): Ikeda, K., Yasukawa, M., et.al.
  • Journal Title: Exp.Hematol 35 Pages: 618-626
  • Peer Reviewed
• [Journal Article] Identification and characterization of a WT1 (Wilms' tumor gene) proteinderived HLA-DRB1*0405-restricted 16-mer helper peptide that promotes the induction and activation of WT1-specific cytotoxic T lymphocytes (2007)
  • Author(s): Fujiki, F., Yasukawa, M., et.al.
  • Journal Title: J.Immunother 30 Pages: 282-293
  • Peer Reviewed
• [Journal Article] Wilms tumor gene WT1 pepide-based immunotherapy induced a minimal response in a patient with advanoed therapy-resistant multiple myeloma (2007)
  • Author(s): Tsuboi A, Yasukawa M, et. al.
  • Journal Title: Int.J.Hematol 86 Pages: 414-417
  • Peer Reviewed
• [Journal Article] Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+regulatory T cells in MRL/lpr mice (2007)
  • Author(s): Hasegawa H, Yasukawa M, et. al.
  • Journal Title: Arthritis Res.Ther 9
  • Peer Reviewed
• [Journal Article] A mitotic kinase TOPK enhanoes odk1/cyclin B1-dependent phosphorylation of PRC1 and promotes cytokinesis (2007)
  • Author(s): Abe Y, Yasukawa M, et. al.
  • Journal Title: J.Mol.Biol 370 Pages: 231-245
  • Peer Reviewed
• [Journal Article] The role of Wilms'tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal hemoglobinuria clone (2007)
  • Author(s): Ikeda K, Yasukawa M, et. al.
  • Journal Title: Exp.Hematol 35 Pages: 618-626
  • Peer Reviewed
• [Journal Article] Identification and characterization of a WT1(Wilms'tumor gene)protein-derived HLA-DRB1^*0405-restricted 16-mer helper peptide that proxnotes the induction and activation of WT1-specific cytotoxic T lymphocytes (2007)
  • Author(s): Fujiki F, Yasukawa M, et. al.
  • Journal Title: J.Immunother 30 Pages: 282-293
  • Peer Reviewed
• [Journal Article] HBZ is an immunogenic protein but not a target antigen for HTLV-1-specific cytotoxic T lymphocytes
  • Author(s): Suemori, K., Yasukawa, M., et.al.
  • Journal Title: J.Gen. Virol. (in press)
  • Peer Reviewed
• [Journal Article] Identification of a novel epitope derived from CML66 which is recognized by anti-leukaemia cytotoxic T lymphocytes
  • Author(s): Suemori, K., Yasukawa, M., Yakushijin, Y., et.al.
  • Journal Title: Br.J.Haematol (in press)
  • Peer Reviewed
• [Journal Article] Clinical efficacy of WT1 peptide vaccination in patients with acute myelogenous leukemia and myelodysplastic syndrome
  • Author(s): Yasukawa, M., Yakushijin, Y., et.al.
  • Journal Title: Am.J.Hematol (in press)
  • Peer Reviewed
• [Journal Article] Clinical significance of co-expression of CD21 and LFA-1 in non-Hodgkin's B-cell lymphoma
  • Author(s): Tanimoto, K., Yakushijin, Y., Yasukawa, M., et.al.
  • Journal Title: Int. J.Hematol (in press)
  • Peer Reviewed
• [Presentation] Aurora-A kinase : A novel target of cellular immunotherapy for humanleukemia (2008)
  • Author(s): Ochi, T., Yasukawa, M., et al
  • Organizer: 50th American Society of Hermatology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-07
• [Presentation] Integrin β3 membrane-proximal and-distal residues cooperatively regulate talin-mediated α〓bβ3 activation (2008)
  • Author(s): Yamanouchi, J., Yasukawa, M., et.al.
  • Organizer: 50th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-06
• [Presentation] Clinical significance of CD21 Co-Expression with LFA-1 in Non-Hodgkin's B-cell lymphoma (2008)
  • Author(s): Tanimoto, K., Yasukawa, M., et.al.
  • Organizer: 50th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-06
• [Presentation] Aurora-A kinase : A novel target of cellular immunotherapy for human leukemia (2008)
  • Author(s): Ochi, T., Yasukawa, M. et.al.
  • Organizer: 50th American Society ofHematology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-06
• [Presentation] Integrin β3 membrane-proximal and - distal residues cooperativelyregulate talin-mediated α II bβ3 activation (2008)
  • Author(s): Yamanouchi, J., Yasukawa, M., et al.
  • Organizer: 50th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-06
• [Presentation] Clinical significance of CD21 Co-Expression with LFA-1 in Non-Hodgkin's B-cell limphoma (2008)
  • Author(s): Tanimoto, K., Yasukawa, M., et al.
  • Organizer: 50th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-06
• [Presentation] Zinc finger protein 521/early hematopoietic zinc finger proteinの赤血球分化における役割 (2008)
  • Author(s): 松原悦子、安川正貴、他
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Development of anti-leukemic immunotherapy targeting Aurora-A kinase (2008)
  • Author(s): Ochi, T., Yasukawa, M., et.al.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Establishment and characterization of a novel CD8+T cell line with cytotoxicity via perforin / granzyme B. (2008)
  • Author(s): Suemori, K., Yasukawa, M., et.al.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Zinc finger protein 521 / early hematopoietic zinc finger proteinの赤血球分化における役割 (2008)
  • Author(s): 松原悦子, 安川正貴, 他
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Establishment and characterization of a novel CD8+ T cell line with cytotoxicity via perforin / granzyme B (2008)
  • Author(s): Suemori, K., Yasukawa, M. etal.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Zinc finger protein 521 の赤血球分化における制御機構の解析 (2008)
  • Author(s): 松原悦子, 安川正貴, 他
  • Organizer: 第70回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-24
• [Presentation] 腫瘍関連抗原CML66の臨床的有用性 (2008)
  • Author(s): 末盛浩一郎, 安川正貴, 他
  • Organizer: 第70回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-12
• [Presentation] Aurora-A kinaseを標的とした抗白血病免疫療法の開発 (2008)
  • Author(s): 越智俊元、安川正貴、他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] 腫瘍関連抗原CML66の臨床的有用性 (2008)
  • Author(s): 末盛浩一郎、安川正貴、他
  • Organizer: 70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] Zinc finger protein 521の赤血球分化における制御機構の解析 (2008)
  • Author(s): 松原悦子、安川正貴、他
  • Organizer: 70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] Aurora-A kinaseを標的とした抗白血病免疫療法の開発 (2008)
  • Author(s): 越智俊元, 安川正貴, 他
  • Organizer: 第70回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] Cytotoxic T-lymphocytes harnessing CML66 can kill human myeloid leukemia cells in vitro (2007)
  • Author(s): Suemori K, Yasukawa M, et. al.
  • Organizer: The 49^<th> Anmnual Meeting of American Society of Hematology
  • Place of Presentation: Atlanta,Georgia,U.S.A.
  • Year and Date: 2007-12-09
• [Presentation] Therapeutic effect of CXCR3-expressing regulatory T cells on liver and intestinal dameges in a murine acute GVHD model (2007)
  • Author(s): Yamanouchi J, Yasukawa M, et. al.
  • Organizer: The 49^<th> Anmnual Meeting of American Society of Hematology
  • Place of Presentation: Atlanta,Georgia,U.S.A.
  • Year and Date: 2007-12-09
• [Presentation] Aurora-A kinase: A novel target for the immunotherapy against human leukemias (2007)
  • Author(s): Ochi T, Yasukawa M, et. al.
  • Organizer: The 49^<th> Anmnual Meeting of American Society of Hematology
  • Place of Presentation: Atlanta,Georgia,U.S.A.
  • Year and Date: 2007-12-08
• [Presentation] ヒト細胞傷害性T細胞が認識するAurora-A由来エピトープの同定 (2007)
  • Author(s): 越智 俊元、安川 正貴, 他
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-11
• [Presentation] 腫瘍関連抗原CML66特異的細胞傷害性T細胞の誘導と機能解析 (2007)
  • Author(s): 末盛 浩一郎、安川 正貴、 他
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-11
• [Presentation] Induction and functional analysis of CML66-specific cytotoxic T lymphocytes (2007)
  • Author(s): Suemori K, Yasukawa M, et. al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-05
• [Presentation] Identification of an epitope derived from Aurora-A kinase which induces leukemia-specific CTL (2007)
  • Author(s): Ochi T, Yasukawa M, et. al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-03
• [Book] Oncogene proteins : Targets for cancer immuno-cell therapy. Oncogene proteins : Structures, Functions and Analyses (2008)
  • Author(s): Fujiwara, H., Yasukawa, M.
  • Publisher: Nova Biomedical Books. New York
• [Book] Oncogene proteins : Structures, Functions and Analyses (2008)
  • Author(s): Fujiwara, H., Yasukawa, M.
  • Total Pages: 31
  • Publisher: Qncogene proteins : Targets for cancer immuno-cell therapy
• [Book] 造血器腫瘍「細胞免疫療法総論」 (2007)
  • Author(s): 安川 正貴
  • Publisher: 日本臨床社
• [Book] 造血器腫瘍「細胞免疫療法各論」 (2007)
  • Author(s): 安川 正貴
  • Publisher: 日本臨床社
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/int.m
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/int.medl/index.htm