Development of new cancer immunotherapy aiming activation of both anti-tumor killer and helper T cells

• Project/Area Number: 24300334
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Kumamoto University
• Principal Investigator: NISHIMURA Yasuharu 熊本大学, 大学院生命科学研究部, 教授 (10156119)
• Co-Investigator(Kenkyū-buntansha): IRIE Atsushi 熊本大学, 大学院生命科学研究部, 講師 (30250343)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: がん免疫療法 / がん抗原 / ペプチドワクチン / キラーＴ細胞 / ヘルパーＴ細胞 / iPS細胞 / キラーT細胞 / ヘルパーT細胞 / ヒトiPS細胞 / iPS樹状細胞 / 人工抗原提示細胞

Outline of Final Research Achievements

Two tumor-associated antigens, LY6K- and IMP3-derived long peptides (LP) that can be presented to CD4+ type 1 T helper (Th1) cells through multiple HLA class II molecules frequently observed in the Japanese population were identified. Using HLA-A2/A24-transgenic mice, vaccination of those LPs including short peptides (SP) that can activate tumor-reactive cytotoxic T lymphocytes (CTL) more efficiently induced CTLs than SP-vaccination did, suggesting the effectiveness of LPs for the improvement of anti-tumor immunotherapy.
Aiming the sufficient supply of antigen presenting cells, a protocol to produce large amount of dendritic cells (DC) from proliferative myeloid-lineage cells (ML) derived from human iPS cells was established. Furthermore, using the TAP-deficient ML, iPS-ML-DC that can escape from the recognition by the alloreactive CTLs was established. These iPS-ML-DC could efficiently present antigenic peptides to both CTLs and Th cells.

Research Products

• [Journal Article] Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFN-γ-dependent cell cycle arrest. (2016)
  • Author(s): Shiina S, Ohno M, Ohka F, Kuramitsu S, Yamamichi A, Kato A, Motomura K, Tanahashi K, Yamamoto T, Watanabe R, Ito I, Senga T, Hamaguchi M, Wakabayashi T, Kaneko MK, Kato Y, Chandramohan V, Bigner DD, Natsume A.
  • Journal Title: Cancer Immunology Research Volume: 4(3) Pages: 259-268
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A clinical trial of multiple peptides vaccination for advanced head and neck cancer patients induced immune responses and prolonged OS. (2015)
  • Author(s): Yoshitake, Y., Nishimura Y., Nakamura Y., and Shinohara, M.
  • Journal Title: OncoImmunology Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. (2015)
  • Author(s): Nishimura, Y., Tomita, Y., Yuno, A., Yoshitake, Y., and Shinohara, M.
  • Journal Title: Cancer Science Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phase II clinical trial of multiple peptide vaccination for advanced head and neck cancer patients with induced immune responses and a prolonged OS. (2015)
  • Author(s): Yoshitake, Y., Fukuma, D., Yuno, A., Hirayama, M., Nakayama, H., Tanaka. T., Nagata, M., Takamune, Y., Kawahara, K., Nakagawa, Y., Yoshida, R., Hirosue, A., Ogi, H., Hiraki, A. , Jono, H., Hamada, A., Yoshida, K., Nishimura, Y., Nakamura, Y., Shinohara, M.
  • Journal Title: Clin. Can. Res. Volume: 21 Pages: 312-21
  • DOI: 10.1158/1078-0432.ccr-14-0202
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells (2015)
  • Author(s): Ikeda T., Hirata S., Takamatsu K., Haruta M., Tsukamoto H., Ito T., Uchino M., Ando Y., Nagafuchi S., Nishimura Y., Senju S.
  • Journal Title: PLos One Volume: 9
  • DOI: 10.1371/journal.pone.0115198
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of immunogenic LY6K long peptide encompassing both CD4+ and CD8+ T-cell epitopes and eliciting CD4+ T-cell immunity in patients with malignant disease (2014)
  • Author(s): Tomita, Y.*, Yuno, A.*, Tsukamoto, H., Senju, S., Kuroda, Y., Hirayama, M., Imamura, Y., Yatsuda, J., Sayem, M. A., Irie, A., Hamada A., Jono, H., Yoshida, K., Tsunoda, T, Daigo, Y., Kohrogi, H., Yoshitake, Y., Nakamura,Y., Shinohara, M., Nishimura, Y.
  • Journal Title: Oncoimmunology Volume: 3
  • DOI: 10.4161/onci.28100
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Therapy of peritoneally disseminated colon cancer by TAP-deficient ES cell-derived macrophages in allogeneic recipients. (2014)
  • Author(s): Haga, E., Endo, Y., Haruta, M., Koba, C., Matsumura, K., Takamatsu, K., Ikeda, T., Nishimura, Y., and Senju, S.
  • Journal Title: Journal of Immunotherapy Volume: 193 Pages: 2024-2033
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Application of iPS cell-derived macrophages to cancer therapy. (2014)
  • Author(s): Senju, S., Koba, C., Haruta, M., Matsunaga, Y., Matsumura, K., Haga, E., Sasaki, Y., Ikeda, T., Takamatsu, K., and Nishimura, Y.
  • Journal Title: OncoImmunoogy Volume: 14
  • DOI: 10.4161/onci.27927
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of CDCA1-derived long peptides bearing both CD4+ and CD8+ T-cell epitopes: CDCA1-specific CD4+ T-cell immunity in cancer patients. (2014)
  • Author(s): Tomita Y, Yuno A, Tsukamoto H, Senju S, Yo shimura S, Osawa R, Kuroda Y, Hirayama M, Irie A, Hamada A, Jono H, Yoshida K, Tsunoda T, Kohrogi H, Yoshitake Y, Nakamura Y, Shinohara M, Nishimura Y
  • Journal Title: International Journal of Cancer Volume: 134 Pages: 352-366
  • DOI: 10.1002/ijc.28376
  • Peer Reviewed
• [Journal Article] CTLとTh1細胞を同時に活性化できるがん抗原ペプチドワクチン療法の開発 (2014)
  • Author(s): 湯野 晃、冨田雄介、西村泰治
  • Journal Title: がん分子標的治療 Volume: 12 Pages: 65-70
• [Journal Article] iPS細胞から分化させた樹状細胞とマクロファージによるがん治療 (2014)
  • Author(s): 千住 覚、西村泰治
  • Journal Title: 臨床免疫・アレルギー科 Volume: 61 Pages: 303-310
• [Journal Article] Long peptides-based cancer immunotherapy targeting both tumor antigen-specific CD4+ and CD8+ T cells through cross-presentation. (2013)
  • Author(s): Tomita, Y., and Nishimura, Y.
  • Journal Title: OncoImmunology Volume: 2
  • DOI: 10.4161/onci.25801
  • Peer Reviewed
• [Journal Article] TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen presenting cells. (2013)
  • Author(s): Haruta, M. et al.
  • Journal Title: GeneTherapy Volume: 20 Pages: 504-513
  • DOI: 10.1038/gt.2012.59
  • Peer Reviewed
• [Journal Article] Therapeutic effect of human iPS-cell–derived myeloid cells expressing IFN-β against peritoneally disseminated cancer in xenograft models. (2013)
  • Author(s): Koba, C., Haruta, M., Matsunaga, Y., Matsumura, K., Haga, E., Sasaki, Y., Ikeda, T., Takamatsu, K., Nishimura, Y., and Senju, S.
  • Journal Title: PLOS ONE Volume: 8
  • DOI: 10.1371/journal.pone.0067567
  • Peer Reviewed
• [Journal Article] Generation of a large number of functional dendritic cells from human monocytes expanded by forced expression of cMYC plus BMI1. (2013)
  • Author(s): Haruta, M., Tomita, Y., Imamura, Y., Matsumura, K., Ikeda, T., Takamatsu, K., Nishimura,Y., and Senju, S.
  • Journal Title: Human Immunology Volume: 74 Pages: 1400-1408
  • DOI: 10.1016/j.humimm.2013.05.017
  • Peer Reviewed
• [Journal Article] cDNAマイクロアレイ解析とHALトランスジェニックマウスを利用した理想的な腫瘍抗原ペプチドワクチン療法の開発 (2013)
  • Author(s): 冨田雄介、西村泰治
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 785-793
• [Journal Article] HLA多型を考慮したがん免疫療法の開発 (2013)
  • Author(s): 千住 覚、冨田雄介、入江厚、西村泰治
  • Journal Title: 血液フロンティア Volume: 23 Pages: 1081-1089
• [Journal Article] Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. (2013)
  • Author(s): Tsukamoto, H., Nishikata, R., Senju, S. and Nishimura, Y.
  • Journal Title: Cancer. Immunol Res. Volume: 1 Pages: 64-76
  • DOI: 10.1158/2326-6066.cir-13-0030
  • Peer Reviewed
• [Journal Article] HLA多型を考慮したがん免疫療法の開発(日本組織適合性学会誌 20号) (2013)
  • Author(s): 冨田雄介、千住覚、入江厚、西村泰治
  • Journal Title: 日本組織適合性学会誌 Volume: 20 Pages: 45-56
• [Presentation] An IMP-3-derived long peptide encompassing CTL and promiscuous Th cell epitopes can be efficiently cross-presented by using a novel liposome. (2014)
  • Author(s): Hirayama, M., Tomita, Y., Yuno, A., Mohammad Abu Sayem.,Tsukamoto, H., Senju, S., Yoshitake, Y., Shinohara, M., Nishimura, Y.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Efficient crosspresentaion of TAA-derived long peptides encompassing CTL and promiscuous Th cell epitopes using a novel liposome (2014)
  • Author(s): Md Abu Sayem, Tomita, Y., Yuno, A., Hirayama, M., Tsukamoto, H., Senju, S., Nakatsura, T., Nishimura, Y.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Cancer Immunotherapy Using Novel Tumor-associated Antigenic Peptides and Human iPS Cell-derived Dendritic Cells (2014)
  • Author(s): Yasuharu Nishimura
  • Organizer: 45th International Symposium of the Princess Takamatsu Cancer Research Fund
  • Place of Presentation: パレスホテル（東京都）
  • Year and Date: 2014-11-18 – 2014-11-20
  • Invited
• [Presentation] 癌胎児性抗原IMP-3由来のCTLとTh細胞の誘導活性を併せ持つ癌抗原ペプチドの同定 (2014)
  • Author(s): 平山真敏、冨田雄介、湯野晃、塚本博丈、千住覚、MD Abu Sayem、吉武義泰、濱田哲暢、城野博史、角田卓也、中村祐輔、篠原正徳、西村泰治
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 腫瘍関連抗原特異的なCTLとTh1細胞を活性化するTh細胞エピトープの同定 (2014)
  • Author(s): 湯野晃、冨田雄介、平山真敏、福間大喜、吉武義泰、尾木秀直、中山秀樹、平木昭光、角田卓也、醍醐弥太郎、中村祐輔、西村泰治、篠原正徳
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 癌胎児性抗原IMP-3由来のCTLとTh1細胞の誘導活性を併せ持つ単一癌抗原ペプチドの同定 (2014)
  • Author(s): 平山真敏、冨田雄介、湯野晃、塚本博丈、千住覚、Mohammad Abu Sayem、吉武義泰、福間大喜、吉田浩二、角田卓也、中村祐輔、篠原正徳、西村泰治
  • Organizer: 第23回日本組織適合性学会大会
  • Place of Presentation: 長崎大学医学部・坂本キャンパス（長崎市）
  • Year and Date: 2014-09-13 – 2014-09-15
• [Presentation] Promiscuous oncoantigenic long peptides activating both tumor-reactive Th1 cells and CTLs (2014)
  • Author(s): Yasuharu NISHIMURA, Yusuke TOMITA, Akira YUNO, Hirotake TSUKAMOTO, Satoru SENJUU, Atsushi IRIE, Yasuhiro KURODA, Akinobu HAMADA, Hirofumi JONO, Koji YOSHIDA, Takuya TSUNODA, Yoshihiro YOSHITAKE, Yusuke NAKAMURA, Masanori SHINOHARA
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール（愛媛県松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
  • Invited
• [Presentation] 癌胎児性抗原IMP-3由来のCTLとTh1細胞の誘導活性を併せ持つ単一癌抗原ペプチドの同定 (2014)
  • Author(s): 平山真敏、冨田雄介、湯野晃、塚本博丈、千住覚、Mohammad Abu Sayem、吉武義泰、福間大喜、角田卓也、吉田浩二、中村祐輔、篠原正徳、西村泰治
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール（愛媛県松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Long peptide-based cancer immunotherapy targeting both tumor antigen-specific CTLs and Th1 cells (2014)
  • Author(s): Yasuharu Nishimura
  • Organizer: Cancer Immunotherapy Annual Meeting
  • Place of Presentation: Rheingold Halle Congress Center, Mainz, Germany
  • Year and Date: 2014-05-06 – 2014-05-08
  • Invited
• [Presentation] Cancer testis antigens-specific CD4+ T-cell immunity augmented by CTL-epitopes vaccination in cancer patients. (2013)
  • Author(s): Tomita, Y., Yuno, A., Yoshitake, Y., Tsukamoto, H., Irie, A., Senju, S., Yoshida, K., Tsunoda, T., Nakamura, Y., Shinohara, M., Nishimura, Y.
  • Organizer: AACR (American Association for Cancer Research) Annual Meeting 2013
  • Place of Presentation: Walter E. Washington Convention Center（アメリカ合衆国）
• [Presentation] TAP2欠損iPS-MLを基盤とするあらゆるHLA型に対応可能な樹状細胞産生システム (2013)
  • Author(s): 千住 覚、春田 美和、冨田 雄介、湯野 晃、松村 桂子、池田 徳典、西村 泰治
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Th1/CTLエピトープが共存する新規CT抗原ペプチドの同定とCTL誘導ペプチド接種患者における特異的Th細胞の増加 (2013)
  • Author(s): 西村 泰治、冨田 雄介、湯野 晃、塚本 博丈、千住 覚、入江 厚、黒田 泰弘、濱田 哲暢、吉田 浩二、角田 卓也、吉武 義泰、中村 祐輔、篠原 正徳
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Cancer therapy with human iPS cell-derived immune cells. (2013)
  • Author(s): Senju, S., Haruta, M., Matsumura, K., and Nishimura, Y.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
• [Presentation] がん抗原ペプチドを用いたがん免疫療法の橋渡し研究 (2012)
  • Author(s): 西村 泰治
  • Organizer: 第50回熊本大学大学院生命科学研究部・化血研ジョイントセミナー
  • Place of Presentation: 熊本大学
  • Year and Date: 2012-12-18
• [Presentation] Developmental of HLA-DR4 transgenic mice useful for identification of CD4+T cell epitope of tumor-associated antigens. (2012)
  • Author(s): 矢津田 旬二
  • Organizer: 第41回日本免疫学会学術総会2012年12月5日
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-12-06
• [Presentation] Identification of a promiscuous LY6K-derived CD4+T cell epitopethat can induce CTLs both in vitro and in vivo. (2012)
  • Author(s): 湯野 晃
  • Organizer: 第41回日本免疫学会学術総会2012年12月5日
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-12-05
• [Presentation] Cancer Immunotherapy Using Ideal Tumor-Associated Antigenic Peptidesand Human iPS Cell-Derived Dendritic Cells. (2012)
  • Author(s): Senju, S., et al.
  • Organizer: Centennial of Hashimoto Disease
  • Place of Presentation: アクロス福岡(福岡市)
  • Year and Date: 2012-12-03
• [Presentation] 理想的がん抗原のCTLエピトープを含むTh1細胞エピトープペプチドによる効率良い抗腫瘍免疫の誘導 (2012)
  • Author(s): 西村 泰治
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2012-09-19
• [Presentation] 新規癌精巣抗原LY6K由来のCTL誘導活性を有するTh1細胞エピトープの同定 (2012)
  • Author(s): 湯野 晃
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2012-09-19
• [Presentation] CD4+T細胞が認識するがん抗原ペプチドを迅速に同定できるHLA-DR4トランスジェニックマウスの樹立 (2012)
  • Author(s): 矢津田 旬二
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2012-09-19
• [Presentation] HLA-DR4拘束性CD4+Th細胞に抗原提示機能を有するHLA-DR4トランスジェニツクマウスの樹立 (2012)
  • Author(s): 入江 厚
  • Organizer: 第21回日本組織適合性学会大会
  • Place of Presentation: 明治大学(東京都)
  • Year and Date: 2012-09-16
• [Presentation] 腫瘍関連抗原CDCA1由来のCTL誘導活性を併せ持つヘルパーT細胞エピトープの同定 (2012)
  • Author(s): 冨田 雄介
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 北海道大学(札幌市)
  • Year and Date: 2012-07-26
• [Presentation] 新規癌精巣抗原LY6K由来のCTL誘導活性を有するTh1細胞エピトープの同定 (2012)
  • Author(s): 湯野 晃
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 北海道大学(札幌市)
  • Year and Date: 2012-07-26
• [Presentation] Establishment of HLA-DR4 (HLA-DRA/HLA-DRB1*04:05) transgenic miceuseful for rapid screening of HLA-DR4-restricted CD4+ T cell epitopePeptides (2012)
  • Author(s): 入江 厚
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 北海道大学(札幌市)
  • Year and Date: 2012-07-26
• [Presentation] がん免疫療法の臨床橋渡し研究の進展-我々の経験から- (2012)
  • Author(s): 中面 哲也
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 北海道大学(札幌市)
  • Year and Date: 2012-07-26
• [Presentation] TAP-deficient human iPS cell-derived myeloid cell lines as cell sourcefor dendritic cells. (2012)
  • Author(s): Senju, S., et al.
  • Organizer: International Society for Stem Cell Research10th Annual Meeting,
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2012-06-13
• [Presentation] Cancer immunotherapy using ideal tumor-associated antigenic peptidesand human iPS cell-derived dendritic cells (2012)
  • Author(s): Nishimura, Y., et al.
  • Organizer: The 16th International HLA and ImmunogeneticsConference
  • Place of Presentation: BT Convention Centre(英国・リバプール)
  • Year and Date: 2012-06-02
• [Presentation] Targeted disruption of the TAP2 gene in human iPS cells and generationof an infinite dendritic cell source that is applicable to vaccination therapyirrespective of HLA types of the patients (2012)
  • Author(s): Senju, S., et al.
  • Organizer: The 16th International HLA and ImmunogeneticsConference
  • Place of Presentation: BT Convention Centre(英国・リバプール)
  • Year and Date: 2012-06-02
• [Presentation] Identification of novel tumor-associated antigenic peptides recognized bytumor-reactive and HLA-A2- or A24-restricted cytotoxic T-lymphocytesuseful for immunotherapy of lung cancer. (2012)
  • Author(s): Tomita, Y., et al
  • Organizer: The 16th International HLA and ImmunogeneticsConference
  • Place of Presentation: BT Convention Centre(英国・リバプール)
  • Year and Date: 2012-06-01
• [Remarks] 熊本大学大学院生命科学研究部 免疫識別学分野
  • URL: http://www.immgenet.jp/
• [Remarks] 熊本大学大学院生命科学研究部免疫識別学分野
  • URL: http://www.immgenet.jp/
• [Patent(Industrial Property Rights)] GPC3 EPITOPE PEPTIDES FOR TH1 CELLS AND VACCINES CONTAINING THE SAME (2014)
  • Inventor(s): 西村泰治、冨田雄介、大沢龍司
  • Industrial Property Rights Holder: 西村泰治、冨田雄介、大沢龍司
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-09
  • Application Year: 2014
• [Patent(Industrial Property Rights)] CDCA1 EPITOPE PEPTIDES FOR TH1 CELLS AND VACCINES CONTAINING THE SAME (2013)
  • Inventor(s): 西村泰治、冨田雄介、大沢龍司
  • Industrial Property Rights Holder: オンコセラピー・サイエンス株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-07-09
  • Application Year: 2013
  • Overseas
• [Patent(Industrial Property Rights)] LY6K epitope peptides for Th1cells and vaccines containing the same (2012)
  • Inventor(s): 西村泰治、冨田雄介、大沢隆司
  • Industrial Property Rights Holder: オンコセラピー・サイエンス株式会社
  • Filing Date: 2012-07-10
  • Application Year: 2012
  • Overseas