多価性がんワクチン

2009 年度 研究成果報告書

• 研究課題/領域番号: 17016031
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 三重大学
• 研究代表者: 珠玖 洋 三重大学, 大学院・医学系研究科, 寄付講座教員・産学官連携講座教員 (80154194)
• 研究分担者: 影山 愼一 三重大学, 大学院・医学系研究科, 准教授 (80194695)
• 研究期間 (年度): 2005 – 2009
• キーワード: 癌・精巣抗原 / キラーT細胞 / ヘルパーT細胞 / マルチファンクション性T細胞 / ペプチド抗原 / GITR / TCR遺伝子改変T細胞

研究概要

(1) 腫瘍特異的T細胞の生体内動態と機能解析:GITR刺激による抗腫瘍効果増強及びその機序と、抗腫瘍免疫におけるCD8+T細胞のマルチファンクション性の重要性を見出した。(2) 動物モデルにおける多価性がんワクチン有効性検証:GITR刺激によるがんワクチン増強を確認し、TCR遺伝子導入T細胞を開発しその輸注療法の有効性を確認した。(3) 臨床応用可能な抗原ペプチド群同定:MAGE-A4, NY-ESO-1, SAGE由来のCD8^+及びCD4^+T細胞エピトープ群を同定した。

研究成果

• [雑誌論文] Tumor progression inhibits the induction of multifunctionality in adoptively transferred tumor-specific CD8+ T cells (2009)
  • 著者名/発表者名: Imai N., Ikeda H., Tawara I., Shiku H
  • 雑誌名: Eur. J. Immunol 39 ページ: 241-53
  • 査読あり
• [雑誌論文] Rapid alphabeta TCR-mediated responses in gammadelta T cells transduced with cancer-specific TCR genes (2009)
  • 著者名/発表者名: Hiasa A., Nishikawa H., Hirayama M., Kitano S., Okamoto S., Chono H., Yu SS., Mineno J., Tanaka Y., Minato N., Kato I., Shiku H
  • 雑誌名: Gene Ther 16 ページ: 620-8
  • 査読あり
• [雑誌論文] Glucocorticoid-induced tumor necrosis factor receptor stimulation enhances the multifunctionality of adoptively transferred tumor antigen-specific CD8 T cells with tumor regression (2009)
  • 著者名/発表者名: Imai N., Ikeda H., Tawara I., Wang L., Wang L., Nishikawa H., Kato T., Shiku H
  • 雑誌名: Cancer Sci 100 ページ: 1317-25
  • 査読あり
• [雑誌論文] Antibody responses against NY-ESO-1 and HER2 antigens in patients vaccinated with combinations of cholesteryl pullulan (CHP)-NY-ESO-1 and CHP-HER2 with OK-432 (2009)
  • 著者名/発表者名: Aoki M., Ueda S., Nishikawa H., Kitano S., Hirayama M., Ikeda H., Toyoda H., Tanaka K., Kanai M., Takabayashi A., Imai H., Shiraishi T., Sato E., Wada H., Nakayama E., Takei Y., Katayama N., Shiku H., Kageyama S
  • 雑誌名: Vaccine 27 ページ: 6854-61
  • 査読あり
• [雑誌論文] Improved Expression and Reactivity of Transduced Tumor-Specific TCRs in Human Lymphocytes by Specific Silencing of Endogenous TCR (2009)
  • 著者名/発表者名: Okamoto S., Mineno J., Ikeda H., Fujiwara H., Yasukawa M., Shiku H., Kato I
  • 雑誌名: Cancer Res 69 ページ: 9003-11
  • 査読あり
• [雑誌論文] Differential Regulatory function of resting and preactivated allergen-specific CD4+CD25+ regulatory T cells in Th2-type airway inflammation (2008)
  • 著者名/発表者名: Saito K., Torii M., Ma N., Tsuchiya T., Wang L., Hori T., Nagakubo D., Nitta N., Kanegasaki S., Hieshima K., Yoshie O., Gabazza EC., Katayama N., Shiku H., Kuribayashi K., Kato T
  • 雑誌名: J. Immunol. 181 ページ: 6889-97
  • 査読あり
• [雑誌論文] Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling (2008)
  • 著者名/発表者名: Nishiakwa H., Kato T., Hirayama M., Orito Y., Sato E., Harada N., Gnjastic S., Old LJ., Shiku H
  • 雑誌名: Cancer Res 68 ページ: 5948-54
  • 査読あり
• [雑誌論文] Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient (2008)
  • 著者名/発表者名: Tsuji K., Hamada T., Uenaka A., Wada H., Sato E., Isobe M., Asagoe K., Yamasaki O., Shiku H., Ritter G., Murphy R., Hoffman EW., Old LJ., Nakayama E., Iwatsuki K
  • 雑誌名: Cancer Immunol. Immunother 57 ページ: 1429-37
  • 査読あり
• [雑誌論文] Humoral immune responses in patients vaccinated with 1-146 HER2 Protein complexed with cholesteryl pullulan nanogel(CHP-HER2) (2008)
  • 著者名/発表者名: Kageyama S., Kitano S., Hirayama M., Nagata Y., Imai H., Shiraishi T., Akiyoshi K., Scott A., Murphy R., Hoffman E., Old L., Katayama N., Shiku H
  • 雑誌名: Cancer Science 99 ページ: 601-7
  • 査読あり
• [雑誌論文] Long-term phenotypic, functional and genetic stability of cancer-specific T cell receptor(TCR)αβgenes transduced to CD8^+T cells. (2008)
  • 著者名/発表者名: Hiasa A., Hirayama M., Nishikawa H., Kitano S., Nukaya I., Yu SS., Mineno J., Kato I., Shiku H.
  • 雑誌名: Gene Ther 15 ページ: 695-9
  • 査読あり
• [雑誌論文] Induction of regulatory T cell-resistant helper CD4^+T cells by bacterial vector. (2008)
  • 著者名/発表者名: Nishikawa H., Tsuji T., Jager E., Briones G., Ritter G., Old LJ., Galan JE., Shiku H., Gnjatic S
  • 雑誌名: Blood 111 ページ: 1404-12
  • 査読あり
• [雑誌論文] Post immune UV-irradiation induces Tr1-like regulatory T cells that suppress humoral immune responses (2008)
  • 著者名/発表者名: Wang L., Toda M., Saito K., Hori T., Horii T., Shiku H., Kuribayashi K., Kato T
  • 雑誌名: Int. Immunology 20 ページ: 57-70
  • 査読あり
• [雑誌論文] In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines (2006)
  • 著者名/発表者名: Nishikawa H., Sato E., Briones G., Chen LM., Matsuo M., Nagata Y., Ritter G., Jager E., Nomura H., Kondo S., Tawara I., Kato T., Shiku H., Old LJ., Galan JE., Gnjatic S
  • 雑誌名: J. Clin. Invest 116 ページ: 1946-54
  • 査読あり
• [雑誌論文] Generation of peptide-specific CD8(+) T cells by phytohemagglutinin-stimulated antigen-mRNA-transduced CD4(+) T cells (2006)
  • 著者名/発表者名: Naota H., Miyahara Y., Okumura S., Kuzushima K., Akatsuka Y., Hiasa A., Kitano S., Takahashi T., Yuta A., Majima Y., Shiku H
  • 雑誌名: J. Immunol. Methods 314 ページ: 54-66
  • 査読あり
• [雑誌論文] HER2-specific T-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan (2006)
  • 著者名/発表者名: Kitano S., Kageyama S., Nagata Y., Miyahara Y., Hiasa A., Naota H., Okumura S., Imai H., Shiraishi T., Masuya M., Nishikawa M., Sunamoto J., Akiyoshi K., Kanematsu T., Scott AM., Murphy R., Hoffman EW., Old LJ., Shiku H
  • 雑誌名: Clin. Cancer Res 12 ページ: 7397-405
  • 査読あり
• [雑誌論文] Interferon-γcontrols the generation/activation of CD4^+ CD25^+ regulatory T cells in anti-tumor immune response (2005)
  • 著者名/発表者名: Nishikawa H., Kato T., Tawara I., Ikeda H., Kuribayashi K., Allen PM., Schreiber RD., Old LJ., Shiku H
  • 雑誌名: J. Immunol 175 ページ: 4433-40
  • 査読あり
• [雑誌論文] Determination of Cellularly Processed HLA-A2402-Restricted Novel CTL Epitopes Derived from Two Cancer Germ line genes, MAGE-A4 and SAGE. Clin (2005)
  • 著者名/発表者名: Miyahara Y., Naota H., Wang L., Hiasa A., Goto M., Watanabe M., Kitano S., Okumura S., Takemitsu T., Yuta A., Majima Y., Lemonnier FA., Boon T., Shiku H
  • 雑誌名: Cancer Res 11 ページ: 5581-9
  • 査読あり
• [雑誌論文] Accelerated chemically induced tumor development mediated by CD4^+CD25^+ regulatory T cells in wild-type hosts (2005)
  • 著者名/発表者名: Nishikawa H., Kato T., Tawara I., Takemitsu T., Saito K., Wang L., Ikarashi Y., Wakasugi H., Nakayama T., Taniguchi M., Kuribayashi K., Old LJ., Shiku H
  • 雑誌名: Proc. Natl. Acad. Sci. USA 102 ページ: 9253-7
  • 査読あり
• [学会発表] Specific silencing of endogenous TCR with siRNAs in human lymphocytes improved expression and anti-tumor reactivity of transduced tumor-specific TCRs (2009)
  • 著者名/発表者名: Okamoto S, MinenoJ, Ikeda H, Fujiwara H, Yasukawa M, Shiku H, Kato I
  • 学会等名: 24th Annual Meeting of International Society for Biological Therapy of Cancer
  • 発表場所: Washington DC, USA
  • 年月日: 20091028-20091101
• [学会発表] Cancer regression in immunodeficient NOG mice by transfer of human T cellstransduced with MAGE-A4-specificαβtype TCR genes (2008)
  • 著者名/発表者名: Ikeda H, Shirakura Y, Hiasa A, Hirayama M, Nishikawa H, Sato E, Nukaya I, Yu SS, Mineno J, Ito M, Kato I, Shiku H
  • 学会等名: 16th Meeting in the Cancer Research Institute International Cancer Immunotherapy Symposium Siries and the 2008 Meeting of the Cancer Vaccine Consortium
  • 発表場所: NY, USA
  • 年月日: 20080915-20080917
• [学会発表] Appearance of multifunctional CD8+ effector T cell in vivo is a critical determinant of successful tumor eradication (2008)
  • 著者名/発表者名: Imai N, Ikeda H, Tawara S, Mineno J, Kato I, Shiku H
  • 学会等名: 16th Meeting in the Cancer Research Institute International Cancer Immunotherapy Symposium Siries and the 2008 Meeting of the Cancer Vaccine Consortium
  • 発表場所: NY, USA
  • 年月日: 20080915-20080917
• [学会発表] Regulatory T cell-resistant CD8+ T cells induced by GITR signaling (2008)
  • 著者名/発表者名: Nishikawa H, Kato T, Harada N, Gnjatic S, Ritter G, Old LJ, Shiku H
  • 学会等名: 16th Meeting in the Cancer Research Institute International Cancer Immunotherapy Symposium Siries and the 2008 Meeting of the Cancer Vaccine Consortium
  • 発表場所: NY, USA
  • 年月日: 20080915-20080917
• [学会発表] Vaccination with CHP-NY-ESO-1 to esophageal cancer patients elicits high-affinity NY-ESO-1-specific CD8+ CTLs recognizing tumor cells (2008)
  • 著者名/発表者名: Hirayama M, Nishikawa H, Aoki M, Ueda S, Kanai M, Takabayashi A, Sato E, Kageyam S, Shiku H
  • 学会等名: 16th Meeting in the Cancer Research Institute International Cancer Immunotherapy Symposium Siries and the 2008 Meeting of the Canser Vaccine Consortium
  • 発表場所: NY, USA
  • 年月日: 20080915-20080917
• [学会発表] Functional analyses of T cells transduced withMAGE-A4-specificαβtype TCR genes (2008)
  • 著者名/発表者名: Hirayama M, Hiasa A, Nishikawa H, Shirakura Y, Ikeda H, Kitano S, Tajima K, Nukaya I, Yu SS, Mineno J, Ito M, Kato I, Shiku H
  • 学会等名: American Association for Cancer Research 99th Annual Meeting
  • 発表場所: San Diego, USA
  • 年月日: 20080412-20080416
• [学会発表] Rapid ab TCR-mediated responses in gd T cells transduced with cancer-specific TCR genes (2008)
  • 著者名/発表者名: Hiasa A, Nishikawa H, Hirayama M, Kitano S, Okamoto S, Chono H, Yu SS, Mineno J, Tanaka Y, Minato N, Kato I, Shiku H
  • 学会等名: American Association for Cancer Research 99th Annual Meeting
  • 発表場所: San Diego, USA
  • 年月日: 20080412-20080416
• [学会発表] Combination cancer vaccine of CHP-NY-ESO-1 and CHP-HER2 with immuno-adjuvant, OK-432, for chemorefractory metastatic or recurrent esophageal cancer patients (2008)
  • 著者名/発表者名: Ueda S, Aoki M, Nishikawa H, Hirayama M, Kitano S, Hayashi E, Kanai M, Takabayashi A, Shiku H, Kageyama S
  • 学会等名: American Association for Cancer Research 99th Annual Meeting
  • 発表場所: San Diego, USA
  • 年月日: 20080412-20080416
• [学会発表] GITR stimmulation enhances anti-tumor effect of adoptive cell therapy restoring activation of antigen-specific CD8+ T Cells (2007)
  • 著者名/発表者名: Imai N, Ikeda H, Nishikawa H, Yamashita Y, Tawara I, Kato T, Shiku H
  • 学会等名: 15th Cancer Research Institute Annual symposium
  • 発表場所: NY, USA
  • 年月日: 20071004-20071006
• [学会発表] A clinical trial of CHP-HER2 vaccine with adjuvant GM-CSF:A case representing antigen spreading (2007)
  • 著者名/発表者名: Kitano S, Kageyama S, Nishikawa H, Hirayama M, Hiasa A, Ikeda H, Old LJ, Shiku H
  • 学会等名: 15th Cancer Research Institute Annual symposium
  • 発表場所: NY, USA
  • 年月日: 20071004-20071006
• [学会発表] Humoral immune responses in patients vaccinated with HER2 protein complexed with a novel antigen delivery system of cholesteryl pullulan(CHP-HER2) (2006)
  • 著者名/発表者名: Kitano S, Hirayama M, Kageyama S, Nagata Y, Nishikawa H, Scott AM, Murphy R, Hoffman EW, Old LJ, Shiku H
  • 学会等名: 97TH Annual Meeting of American Association for Cancer Reseach
  • 発表場所: Washington DC, USA
  • 年月日: 20060401-20060405
• [学会発表] Ex vivo generation of human peripheral blood monocyte-derived antigen presenting cells (2006)
  • 著者名/発表者名: Katayama N, Shiku H
  • 学会等名: International Symposium on Molecular Cell Biology of Macrophages and Dendritic Cells 2006
  • 発表場所: Tokyo, Japan
  • 年月日: 2006-06-10
• [図書] 内科学書内科学総論 (2009)
  • 著者名/発表者名: 珠玖洋、池田裕明, 他
  • 総ページ数: 34-42
  • 出版者: 中山書店
• [備考]
  • URL: http://www.shikuken.jp/
• [産業財産権] 特異的遺伝子の発現方法 (2008)
  • 発明者名: 峰野純一、岡本幸子、住岡理早、北川正成、珠玖洋、加藤郁之進
  • 権利者名: 国立大学法人三重大学、タカラバイオ株式会社
  • 産業財産権番号: 特許・WO2008/153029(国際公開番号)
  • 出願年月日: 2008-06-10
• [産業財産権] 細胞傷害性Tリンパ球 (2004)
  • 発明者名: 珠玖洋、日浅厚則、奥村悟司、直田浩明、宮原慶裕
  • 権利者名: 国立大学法人三重大学、タカラバイオ株式会社
  • 産業財産権番号: 特許・特願2004-290785、特開2006-101735
  • 出願年月日: 2004-10-01