ムチン分子を標的とした上皮性腫瘍の免疫遺伝子療法

• Project/Area Number: 12217097
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Yamaguchi University
• Principal Investigator: 日野田 裕治 山口大学, 医学部, 教授 (10165128)
• Co-Investigator(Kenkyū-buntansha): 山本 光太郎 山口大学, 医学部, 助手 (50304481) ; 濱中 裕一郎 山口大学, 医学部, 助教授 (40189618) ; 萱野 幸三 山口大学, 医学部, 助手 (90314799) ; 石田 禎夫 札幌医科大学, 医学部, 助手 (20305220)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥57,800,000 (Direct Cost: ¥57,800,000); Fiscal Year 2004: ¥11,100,000 (Direct Cost: ¥11,100,000); Fiscal Year 2003: ¥11,100,000 (Direct Cost: ¥11,100,000); Fiscal Year 2002: ¥11,000,000 (Direct Cost: ¥11,000,000); Fiscal Year 2001: ¥12,600,000 (Direct Cost: ¥12,600,000); Fiscal Year 2000: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: RHAMM / mRNA / dendritic cells / MHC class II / cancer immunotherapy / 樹状細胞 / TRP2 / B16 / EGFP / EL4 / ELISPOT / 免疫遺伝子療法 / MUC1 / ペプチドワクチン / CTL / リポソーム / 膵癌 / O-glycan / GalNAc transferase

Research Abstract

RHAMM (receptor for hyaluronan-mediated motility) mRNAを腫瘍抗原として樹状細胞療法の基礎的検討を行った。本mRNAはマウスの5種類の腫瘍細胞全てで発現していたが、正常組織では胸腺を除いて発現を認めなかった。RHAMMは細胞質内蛋白であるため、MHC class IIによる提示効率を高める目的でTRP-2との融合mRNAを作成した。RHAMM mRNA導入樹状細胞で免疫したマウスの脾細胞には明らかな殺細胞活性が誘導された。この誘導効果は抗CD4抗体投与で消失したが、抗CD8抗体は影響しなかった。EL4皮卞腫瘍(3日モデル)に対しても顕著な増殖抑制効果が観察されたが、この場合も抗CD8抗体ではなく、抗CD4抗体投与によってのみ治療効果が消失した。これらの結果から、本治療モデルにおいてはCD4+T細胞が抗腫瘍効果を発揮していることが示唆された。mRNA導入樹状細胞の臨床試験については、GMP基準準拠のcell processing center (CPC)で実施すべく手順書の作成が順調に進んでいる。さらに、胃癌および大腸癌において、細胞株・臨床検体のいずれにおいても高率にclass II transactivator (CIITA)遺伝子のメチル化が生じていることを明らかにした。このメチル化は5-azacytidineなどの脱メチル化剤によって解除できることから、class II陰性腫瘍のうちCIITAのメチル化が証明される場合は、脱メチル化剤併用免疫療法が有効である可能性がある。

Research Products

• [Journal Article] Therapeutic effect of dendritic cells loaded with a fusion mRNA encoding tyrosinase-related protein 2 and enhanced green fluorescence protein on B16 melanoma. (2004)
  • Author(s): Fukui M. et al.
  • Journal Title: Tumor Biol. 25 Pages: 252-257
• [Journal Article] Monoclonal antibodies as effective therapeutic agents for solid tumors. (2004)
  • Author(s): Hinoda Y. et al.
  • Journal Title: Cancer Sci. 95 Pages: 621-625
  • NAID: 80016809427
• [Journal Article] The current status and issues concerning monoclonal antibody therapy. (2004)
  • Author(s): Hinoda Y.
  • Journal Title: Bull.Yamaguchi Med.School 51 Pages: 41-50
  • NAID: 120000863927
• [Journal Article] Epigenetic inactivation -of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells. (2004)
  • Author(s): Satoh A. et al.
  • Journal Title: Oncogene 23 Pages: 8876-8886
• [Journal Article] Epigenetic inactivation of the SFRP's complements genetic alterations to allow constitutive WNT pathway signaling in human colorectal cancer. (2004)
  • Author(s): Suzuki H. et al.
  • Journal Title: Nature Genet. 36 Pages: 417-422
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• [Publications] Hinoda Y et al.: "Association of Functional Polymorphisms of the Matrix Metalloproteinase (MMP)-1 and MMP-3 Genes with Colorectal Cancer"Int. J. Cancer. 102. 526-529 (2002)
• [Publications] Kodama H. et al.: "Specific and effective targeting cancer immunotherapy with a combination of three bispecific antibodies"Immunology Lett.. 81. 99-106 (2002)
• [Publications] McDermott K.M. et al.: "Overexpression of MUC1 reconfigures the binding properties of tumor cells"Int. J. Cancer. 94. 783-791 (2001)
• [Publications] Kodama H. et al.: "Mutated SEA-D227A-conjugated antibodies greatly enhance antitumor activity against MUC1-expressing bile duct carcinoma"Cancer Immunol. Immunother.. 50. 539-548 (2001)
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• [Publications] Satoh S et al.: "Enhancement of metastatic properties of pancreatic cancer cells by transfer of MUC1 gene encoding an anti-adhesion molecule."Int J Cancer. 88. 507-518 (2000)