がん遺伝子産物由来ペプチド抗原によるがん治療

• Project/Area Number: 12217062
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Mie University
• Principal Investigator: 珠玖 洋 三重大学, 医学部, 教授 (80154194)
• Co-Investigator(Kenkyū-buntansha): 影山 愼一 (影山 慎一) 三重大学, 医学部, 助手 (80194695) ; 渡辺 正人 藤田保健衛生大学, 医学部, 講師 (30220924) ; 片山 直之 三重大学, 医学部, 講師 (20185812)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥202,000,000 (Direct Cost: ¥202,000,000); Fiscal Year 2004: ¥45,000,000 (Direct Cost: ¥45,000,000); Fiscal Year 2003: ¥40,500,000 (Direct Cost: ¥40,500,000); Fiscal Year 2002: ¥40,000,000 (Direct Cost: ¥40,000,000); Fiscal Year 2001: ¥40,500,000 (Direct Cost: ¥40,500,000); Fiscal Year 2000: ¥36,000,000 (Direct Cost: ¥36,000,000)
• Keywords: 癌遺伝子 / 癌ワクチン / キラーT細胞 / ヘルパーT細胞 / HER2 / 疎水化多糖類 / 蛋白抗原 / 抗原デリバリーシステム / 制御性T細胞 / SEREX抗原 / ペプチド / SEREX / CTLエピトープ / ヘルパーエピトープ / 原癌遺伝子 / CTL / DNAワクチン

Research Abstract

1.昨年度に続き、マウス肉腫CMS5腫瘍特異的抗原ペプチド9mに対するT細胞レセプター発現トランスジェニックマウスの系で、抗GITR抗体を、腫瘍接種後に投与した場合に特異的CD8^+T細胞の活性化および分裂が認められると共に、腫瘍の増殖が抑制された。抗GITR抗体は、CD4^+T細胞非存在下でもDUC18のCD8^+T細胞の抗原特異的増殖と活性化を促進し、SCIDマウスの実験系で、CD4^+CD25^-T細胞とCD8^+T細胞による腫瘍増殖抑制を増強した。
2.我々がこれ迄開発検討して来た新規抗原デリバリーシステム、疎水化多糖類との複合体(CHP-HER2)をクリニカルグレードで作製し、第1相試験を行った。予定した9症例の検討を終了し、注射部位の発赤・腫脹を一過性に認めたがその他有害事象は観察されていない。
3.ワクチンを受けた8症例で、投与した組み換えHER2蛋白に対するIgG抗体が免疫後に出現し全ての症例でIgG1抗体が優位であった。抗原mRNA導入自家リンパ球を用いたELISPOT法により、現在までに8症例中5症例で、組み替え蛋白を発現した標的細胞に特異的に反応するCD8^+T細胞またはCD4^+T細胞を、又3症例で両者を検出した。

Research Products

• [Journal Article] Definition of target antigens for naturally occurring CD4^+CD25^+ regulatory T cells. (2005)
  • Author(s): Nishikawa, H.
  • Journal Title: J.Exp.Med. 201 Pages: 681-686
• [Journal Article] Reprogramming of human post-mitotic neutrophils into macrophages by growth factors. (2004)
  • Author(s): Araki, H.
  • Journal Title: Blood 103 Pages: 2973-2980
• [Journal Article] CD21S antigen expression in tumour cells of diffuse large B-cell lymphomas is an independent prognostic factor indicating better overall survival. (2004)
  • Author(s): Ogawa, S.
  • Journal Title: Br.J.Haematol. 125 Pages: 180-186
• [Journal Article] mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. (2004)
  • Author(s): Greiner, J.
  • Journal Title: Int.J.Cancer 108 Pages: 704-711
• [Journal Article] Activities of granulocyte-macrophage colony-stimulating factor and interleukin-3 on monocytes. (2004)
  • Author(s): Suzuki, H.
  • Journal Title: Am.J.Hematol. 75 Pages: 179-189
• [Publications] Nishikawa, H., Shiku, H., et al.: "CD4^+ CD25^+ T cells responding to serologically defined autoantigens suppress antitumor immune responses."Proc.Natl.Acad.Sci.USA.. 100. 10902-10906 (2003)
• [Publications] Wang, L., Shiku, H., et al.: "Essential roles of tumor-derived helper T cell epitopes for an effective peptide-based tumor vaccine."Cancer Immun.. 3. 16 (2003)
• [Publications] Shiku, H.: "Importance of CD4^+ helper T-cells in antitumor immunity."Int.J.Hematol.. 77. 435-438 (2003)
• [Publications] Ishihara, M., Shiku, H., et al.: "Elimination of CD4^+ T cells may overcome suppression of anti-HER2 immune responses in tumor-bearing hosts."Int.J.Oncol.. 22. 1135-1139 (2003)
• [Publications] Kobayashi, T., Shiku, H., et al.: "Microarray reveals differences in both tumors and vascular specific gene expression in de novo CD5^+ and CD5^- diffuse large B-Cell lymphomas."Cancer Res.. 63. 60-66 (2003)
• [Publications] Suguro-Katayama, M., Shiku, H., et al.: "Heterogeneous copy numbers of API2-MALT1 chimeric transcripts in mucosa-associated lymphoid tissue lymphoma."Leukemia. 17. 2508-2512 (2003)
• [Publications] Ikuta, Y., Shiku, H.et al.: "Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex : implications for a polyvalent immuno-cell therapy"Blood. 99. 3717-3724 (2002)
• [Publications] Mukai, K., Shiku, H.et al.: "HER2 peptide-specific CD8(+) T cells are proportionally detectable long after multiple DNA vaccinations"Gene Ther.. 9. 879-888 (2002)
• [Publications] Nishii, K., Shiku, H.et al.: "Adult acute myeloid leukemia cells do not express non-functional Ikaros isoforms"Blood. 100. 3436-3437 (2002)
• [Publications] Yamaguchi, M., Shiku, H.et al.: "De novo CD5+ diffuse large B-cell lymphoma : a clinicopathologic study of 109 patients"Blood. 99. 815-821 (2002)
• [Publications] Masuya, M., Shiku, H.et al.: "The soluble Notch ligand, Jagged-l, inhibits proliferation of CD34+ macrophage progenitors"Int J Hematol.. 75. 269-276 (2002)
• [Publications] Nishikawa, H., Shiku, H.et al.: "Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity"Proc.Natl.Acid Sci.(USA). 98. 14571-14576 (2001)
• [Publications] Araki, H., Shiku, H.et al.: "Efficient ex vivo generation of derisritic cells from CD14^+blood monocytes in the present of human setum albumin for-use in clinical raccine trials"Br.J.Haematol. 114. 681-689 (2001)
• [Publications] Ohnishi, K., Shiku, H.et al.: "Efficient ex vivo generation of human dendentic cells from mobilized CD34^+ pepripheral blood orogenitors"Hematol. 74. 287-296 (2001)
• [Publications] Shiku, H. et al.: "A novel hydrophobized polysaccharide oncoprotein complex raccine for HER2 gene expressing cancer"Biomedical Polymers and Polymer Thrapeutics. 331-337 (2001)
• [Publications] Watanabe, Y., Shiku, H.et al.: "Protein kinase C-catalyzed phosphorylation of an inhibitory phosphoprotein of myosin phosphatase"Blood. 97. 3798-3805 (2001)
• [Publications] Okugawa,T.,Ikuta Y. et al.: "A novel HER2-derived peptide homologous to the mouse kd restricted tumor rejection antigen can…"Eur.J.Immunology. 11. 3338-46 (2000)
• [Publications] Hanson,H.L.,Donermeyer,D,L. et al.: "Eradication of Established Tumors by CD8^+ T cell Adoptive Immunotherapy. "Immunity. 13. 265 (2000)
• [Publications] Ikuta,Y.,Okugawa,T. et al.: "An HER2/neu-derived peptide, a kd-restricted murine tumor rejection antigen, induce…"Int.J.Cancer. 87. 553-558 (2000)
• [Publications] Hitani,H.,Katayma,N. et al: "Activity of interleukin b in the differentiation of monocytes to macrophages and dendritic cells."Br.J.Haematol. 109. 228-295 (2000)
• [Publications] Saus,H.,Kobayashi,T. et al: "Bax overexpression enhances cytochrome c release from mitochondria and sensitizes KATO III…"Int.J.Oncology. 16. 745-749 (2000)
• [Publications] Nakase,K.,Bradstock,K. et al.: "Geographic heterogeneity of cellular characteristics of acute myeloid leukemia a comparative…"Int.J.Hematology. 71. 59-65 (2000)