腫瘍抗原の同定と宿主免疫応答の解析

• Project/Area Number: 12217092
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Okayama University
• Principal Investigator: 中山 睿一 岡山大学, 大学院・医歯学総合研究科, 教授 (60180428)
• Co-Investigator(Kenkyū-buntansha): 小野 俊朗 岡山大学, 自然生命科学研究支援センター, 助教授 (50185641) ; 上中 明子 岡山大学, 大学院・医歯学総合研究科, 助手 (50273967) ; 野口 雄司 岡山大学, 大学院・医歯学総合研究科, 助教授 (10314684)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥82,500,000 (Direct Cost: ¥82,500,000); Fiscal Year 2004: ¥17,000,000 (Direct Cost: ¥17,000,000); Fiscal Year 2003: ¥17,200,000 (Direct Cost: ¥17,200,000); Fiscal Year 2002: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 2001: ¥17,300,000 (Direct Cost: ¥17,300,000); Fiscal Year 2000: ¥16,000,000 (Direct Cost: ¥16,000,000)
• Keywords: がん / 免疫 / がん抗原 / がん・精巣抗原抗 / がんワクチン / 臨床試験 / 免疫モニタリング / 免疫療法 / がん・精巣抗原 / PCR / 抗体 / T細胞 / 癌 / 免疫学 / 癌抗原 / トランスレーショナルリサーチ / CTL認識抗原 / Meth A / MAP / 抗原提示 / 精子蛋白 / CT抗原 / 前立腺癌 / NY-ESO-1 / がん免疫療法 / T細胞抗体 / SEREX

Research Abstract

1.CHP(cholesterol hydrophobized pullulan)は、プルラン鎖に、コレステロールを配したナノパーティクルである。CHPとNY-ESO-1蛋白の複合体をDCにパルスし、健常人から得たCD8T細胞をin vitroで刺激し、特異的な反応の誘導を検討した。2回以上の刺激で特異的CD8T細胞の反応が認められた。同じ、CHP-NY-ESO-1複合体パルスDCを用いてCD4T細胞を刺激して、同様に特異的に反応が誘導されるか否かを検討した。やはり、2回以上の刺激でCD4T細胞の反応が誘導された。オーバーラップペプチドを用いて、DR1501拘束性の新しいエピトープを同定した。このように、DC細胞は、CHP-NY-ESO-1複合体を取り込んで、クラスIおよびIIのいずれのエピトープも発現することを明らかにした。
2.CHP-NY-ESO-1を用いた臨床試験を開始した。臨床試験プロトコルは、ニューヨーク、ラドウィック癌研究所および岡山大学大学院医歯学総合研究科で承認された。第一目的は、安全性およびNY-ESO-1に対する免疫能の検討で、第二目的は、腫瘍の反応を観察することである。2週おきに4回投与する。他に有効な治療法がない進行癌患者を対象とする。現在、参加登録患者は4名で、その内訳は、食道癌(IV期)1名、および前立腺癌(D期)3名である。現在、評価可能患者数は3名であるが、3名ともに強い抗体産生が認められた。抗体認識エピトープの解析では、特に抗原性の強いエピトープが認められた。CD8およびCD4T細胞の反応は、比較的早くから認められた。腫瘍に対してもある程度の効果を認めた。

Research Products

• [Journal Article] quantitative real-time RT-PCR analysis of NY-ESO-1 and LAGE-1a mRNA expression in normal tissues and tumors, and correlation of the protein expression with the mRNA copy number. (2005)
  • Author(s): Sato, S., et al.
  • Journal Title: Int.J.Oncol. 26 Pages: 57-63
• [Journal Article] SSX expression in gynecological cancers and antibody response in patients. (2004)
  • Author(s): Hasegawa, K., et al.
  • Journal Title: Cancer Immunity 4 Pages: 16-16
• [Journal Article] NY-ESO-1 expression and immunogenicity in esophageal cancer. (2004)
  • Author(s): Fujita, S., et al.
  • Journal Title: Clinical Cancer Res. 10 Pages: 6551-6558
• [Journal Article] Over-expression of the testis-specific gene TSGA10 in cancers and its immunogenicity. (2004)
  • Author(s): Tanaka, R., et al.
  • Journal Title: Microbiol.Immunol. 48 Pages: 339-345
• [Journal Article] Analysis of CD8 T cell response by IFNγ ELISPOT and H-2H^d/pRL1a tetramer assays in pRL1a multiple antigen peptide-immunized and RL male 1-bearing BALB/c and (BALB/c x C57BL/6)F_1 mice. (2004)
  • Author(s): Takada, I., et al.
  • Journal Title: Cancer Sci. 95 Pages: 254-259
• [Journal Article] NY-ESO-1 expression and immunogenicity in malignant and benign breast tumors. (2004)
  • Author(s): Sugita, Y., et al.
  • Journal Title: Cancer Res. 64 Pages: 2199-2204
• [Journal Article] Inhibition of RL male 1 tumor growth in BALB/c mice by introduction of the RLakte gene coding for antigen recognized by cytotoxic T lymphocytes and the GM-CSF gene by in vivo electroporation. (2004)
  • Author(s): Tanaka, M., et al.
  • Journal Title: Cancer Sci. 95 Pages: 154-159
• [Journal Article] Immunoscreening of a cDNA library from a lung cancer cell line using autologous patient serum : identification of XAGE-1b as a dominant antigen and its immunogenicity in lung adenocarcinoma. (2004)
  • Author(s): Ali Mohamed Ali ElDib, et al.
  • Journal Title: Int.J.Cancer 108 Pages: 558-563
• [Journal Article] AKAP3 mRNA expression in ovarian cancer and its implication on prognosis. (2004)
  • Author(s): Hasegawa, K., et al.
  • Journal Title: Int.J.Cancer 108 Pages: 86-90
• [Publications] Kuroki, M., et al.: "Repression of bleomycin-induced pneumopathy by tumor necrosis factor"J.Immunol.. 170. 567-574 (2003)
• [Publications] Uenaka, A., et al.: "Cryptic cytotoxic T lymphocyte epitope on a murine sarcoma Meth A generated by exon extension as a novel machanism"J.Immunol.. 170. 4862-4868 (2003)
• [Publications] Hasegawa, K., et al.: "AKAP3 mRNA expression in ovarian cancer and its implication on prognosis"Int.J.Cancer. 108. 86-90 (2004)
• [Publications] Ali Mohamed Ali ElDib, et al.: "Immunoscreening of a cDNA library from a lung cancer cell line using autologous patient serum : identification of XAGE-1b as a dominant antigen and its immunogenicity in lung adenocarcinoma"Int.J.Cancer. 108. 558-563 (2004)
• [Publications] Sugita, Y., et al.: "NY-ESO-1 expression and immunogenicity in malignant and benign breast tumors"Cancer Res.. (in press). (2004)
• [Publications] Takada, I., et al.: "Analysis of CD8 T cell response by IFNγ ELISPOT and H-2H^d/pRL1a tetramer assays in pRL1a multiple antigen peptide-immunized and RL male 1-bearing BALB/c and (BALB/c x C57BL/6)F_1 mice"Cancer Science. (in press). (2004)
• [Publications] Uenaka, A., et al.: "Cryptic cytotoxic T lymphocyte epitope on a murine sarcoma Meth A generated by exon extension as a novel machanism"J. Immunol.. (in press). (2003)
• [Publications] Kuroki, M., et al.: "Repression of bleomycin-induced pneumopathy by tumor necrosis factor"J. Immunol.. 170. 567-574 (2003)
• [Publications] Tawara, I., et al.: "Sequential involvement of two distinct CD4 _t regulatory T cells during the course of transplantable tumor growth and protection from 3-methylcholanthrene-induced tumorgenesis by CD25-depletion"Jpn. J. Cancer Res.. 93. 911-916 (2002)
• [Publications] Sanda, W., et al.: "Immune responses against allogeneic and syngeneic tumors aged C57BL/6 mice"Microbiol. Immunol. 46. 513-529 (2002)
• [Publications] Hata, H, et al.: "Occurrence of tumor antigen pRL1a specific CD8 T cells in spleen cells from syngeneic BALB/c semiallogeneic (BALB/c x C57BL/6)F_1 and allogenic C57BL/6 mice"Int. J. Oncol.. 20. 1019-1025 (2002)
• [Publications] Ota, S., et al.: "Cellular processing of a mulibranched lysine core with tumor antigen peptides and presentation of peptide epitopes recognized by cytotoxic T lymphocytes on antigen presenting cells"Cancer Res.. 62. 1471-1476 (2002)
• [Publications] Hata, H., et al.: "Occurrence of tumor antigen pRL1a specific CD8 T cells in spleen cells from syngeneic BALB/c, semiallogeneic (BALB/c x C57BL/6)F_1 and allogeneic C57BL/6 mice"Int. J. Oncol.. (in press).
• [Publications] Ota, S., et al.: "Cellular processing of a multibranched lysine core with tumor antigen peptides and presentation of peptide epitopes recognized by cytotoxic T lymphocytes on antigen presenting cells"Cancer Res.. (in press).
• [Publications] Uenaka, A., et al.: "ELISPOT cloning of tumor antigens recognized by cytotoxic T-lymphocytes from a cDNA expression library"Cancer Immunity. 1. 8-17 (2001)
• [Publications] Kurashige, T., et al.: "NY-ESO-1 expression and immunogenicity associated with transitional cell carcinoma : correlation with tumor grade"Cancer Res.. 61. 4671-4674 (2001)
• [Publications] Sakamoto, N., et al.: "A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues"Eur. J. Immunol.. 31. 1310-1316 (2001)
• [Publications] Ono, T., et al.: "Identification of proacrosin binding protein sp32 precursor as a human cancer/testis antigen"Proc. Natl. Acad. Sci. USA. 98. 3282-3287 (2001)
• [Publications] Ono,T., et al.: "Identification of proacrosin binding protein sp32 precursor as a new human cancer/testis antigen."Proc.Natl.Acad.Sci.USA. (in press.).
• [Publications] Sakamoto,N., et al.: "A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues."Eur.J.Immunol.. (in press.).
• [Publications] One,T., et al.: "Serological analysis of BALB/c methylcholanthrene sarcoma Meth A by SEREX.Identification of a cancer/testis antigen."Int.J.Cancer. 88. 845-851 (2000)
• [Publications] Shibuya,A., et al.: "Fcα/μ receptor mediates endocytosis of IgM-coated mictobes."Nature immunology. 1. 441-446 (2000)
• [Publications] Kobayashi,Y., et al.: "Expression of MAGE, GAGE and BAGE gene in human liver diseases : utility as molecular markers for hepatocellular carcinoma."J.Hepatol.. 32. 612-617 (2000)