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2010 Fiscal Year Annual Research Report

がんに対する免疫賦活化抗体療法の開発

Research Project

Project/Area Number 22240089
Research InstitutionJuntendo University

Principal Investigator

八木田 秀雄  順天堂大学, 医学部, 准教授 (30182306)

KeywordsDR5 / 4-1BB / CD40 / CTLA-4 / PD-1 / CD27 / Notch2 / OX40
Research Abstract

(1)宿主の免疫抑制系を解除するGITRやOX40に対するアゴニスト抗体あるいはCTLA-4やPD-1に対する阻害抗体とtrimAbの組み合わせを4T1乳がん移植モデル及びMCA発癌モデルに投与し、以下の結果を得た。(1)GITRあるいはOX40刺激またはPD-1阻害は、trimAbによって誘導される所属リンパ節細胞の4T1特異的なIFN-γ産生やCTL活性を増強したが、trimAbの抗腫瘍効果を増強しなかった。(2)逆に、CTLA-4阻害は、trimAbによって誘導される所属リンパ節細胞の4T1特異的なIFN-γ産生やCTL活性を増強しなかったが、trimAbの抗腫瘍効果を増強した。(3)CTLA-4阻害は、MCA発癌モデルにおいてもtrimAbの抗腫瘍効果を増強し、Tregを含むCD4 T細胞を除去してもこの増強は認められた。(4)trimAb単独あるいはtrimAb+抗CTLA-4奏功例においては、腫瘍内のFoxP3陽性CD4 T細胞(Treg)及びGr-1陽性CD11b陽性myeloid-derived suppressor cells(MDSC)の減少とCD8 T細胞の増加が認められた。以上の結果から、抗CTLA-4抗体は、腫瘍局所でのCD8 T細胞の増殖と機能を亢進することによってtrimAbの抗腫瘍効果を増強すると考えられ、抗ヒトCTLA-4抗体(ipilimumab)の有用性が示唆された。(2)マウスCD27に対するアゴニスト抗体を樹立し、EG7白血病あるいはB16-OVAマラノーマ担癌マウスにおいて、抗CD137抗体に匹敵する強い抗腫瘍効果が得られ、主にCD8陽性CTL誘導の増強によることを示した。(3)マウスNotch2に対するアゴニスト抗体を樹立し、EG7担癌マウスにおいてCTL誘導による強い抗腫瘍効果が得られることを示した。(4)OVA, TRP-1あるいはgp100レンチウィルスを用いたワクチン系で誘導された抗原特異的CTLは、腫瘍内ではPD-1の高発現によって不活化されており、PD-1あるいはPD-L1に対する阻害抗体の投与で回復し、強い抗腫瘍効果が得られることを示した。(5)B16メラノーマに対するFvax系で、PD-1とCTLA-4に対する阻害抗体の組み合わせが相乗的に抗腫瘍効果を増強することを示した。

  • Research Products

    (30 results)

All 2010

All Journal Article (20 results) (of which Peer Reviewed: 20 results) Presentation (10 results)

  • [Journal Article] Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules2010

    • Author(s)
      Takeda K, Kojima Y, Uno T, Hayakawa Y, Teng MWL, Yoshizawa H, Yagita H, Geyjo F, Okumura K, Smyth MJ
    • Journal Title

      J Immunol

      Volume: 184 Pages: 5493-5501

    • DOI

      DOI:10.4049/jimmunol.0903033

    • Peer Reviewed
  • [Journal Article] PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.2010

    • Author(s)
      Curran MA, et al
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 107 Pages: 4275-4280

    • Peer Reviewed
  • [Journal Article] Notch2 signaling is required for potent antitumor immunity in vivo.2010

    • Author(s)
      Sugimoto K, et al
    • Journal Title

      J Immunol

      Volume: 184 Pages: 4673-4678

    • Peer Reviewed
  • [Journal Article] PD-1/B7-H1 interaction contributes to the spontaneous acceptance of mouse liver allograft.2010

    • Author(s)
      Morita M, et al
    • Journal Title

      Am J Transplant

      Volume: 10 Pages: 40-46

    • Peer Reviewed
  • [Journal Article] Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function.2010

    • Author(s)
      Kenna TJ, et al
    • Journal Title

      J Immunol

      Volume: 184 Pages: 598-606

    • Peer Reviewed
  • [Journal Article] Plasmacytoid dendritic cells induce IL-10 production in T cells via the Delta-like-4/Notch axis.2010

    • Author(s)
      Kassner N, et al
    • Journal Title

      J Immunol

      Volume: 184 Pages: 550-554

    • Peer Reviewed
  • [Journal Article] Blockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer.2010

    • Author(s)
      Oishi H, et al
    • Journal Title

      Pancreas

      Volume: 39 Pages: 897-903

    • Peer Reviewed
  • [Journal Article] DNAM-1/CD155 interactions promote cytokine NK cell-mediated suppression of poorly immunogenic melanoma metastasis.2010

    • Author(s)
      Chan CJ, et al
    • Journal Title

      J Immunol

      Volume: 184 Pages: 902-911

    • Peer Reviewed
  • [Journal Article] Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts.2010

    • Author(s)
      Quezada SA, et al
    • Journal Title

      J Exp Med

      Volume: 207 Pages: 637-650

    • Peer Reviewed
  • [Journal Article] Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice.2010

    • Author(s)
      Sakanishi T, et al
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 393 Pages: 829-835

    • Peer Reviewed
  • [Journal Article] Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors.2010

    • Author(s)
      Lee S, et al
    • Journal Title

      Cancer Immunol Immunother

      Volume: 59 Pages: 1073-1081

    • Peer Reviewed
  • [Journal Article] Premature terminal exhaustion of Friend virus-specific effector CD8 T cells by rapid induction of multiple inhibitory receptors.2010

    • Author(s)
      Takamura S, et al
    • Journal Title

      J Immunol

      Volume: 184 Pages: 4696-4707

    • Peer Reviewed
  • [Journal Article] Combined treatment with dendritic cells and 5-fluorourasil elicits augmented NK cell-mediated antitumor activity through the tumor necrosis factor-alpha pathway.2010

    • Author(s)
      Nagasaki E, et al
    • Journal Title

      J Immunother

      Volume: 33 Pages: 467-474

    • Peer Reviewed
  • [Journal Article] CD11c+ dendritic cells and B cells contribute to the tumoricidal activity of anti-DR5 antibody therapy in established tumors.2010

    • Author(s)
      Haynes NM, et al
    • Journal Title

      J Immunol

      Volume: 185 Pages: 532-541

    • Peer Reviewed
  • [Journal Article] Resistance of T-cell acute lymphoblastic leukemia (T-ALL) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.2010

    • Author(s)
      Akahane K, et al
    • Journal Title

      Exp Hematol

      Volume: 38 Pages: 885-895

    • Peer Reviewed
  • [Journal Article] Peptide vaccine induces enhanced tumor growth associated with apoptosis induction in CD8+ T cells.2010

    • Author(s)
      Muraoka D, et al
    • Journal Title

      J Immunol

      Volume: 185 Pages: 3768-3776

    • Peer Reviewed
  • [Journal Article] Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8+ T cells.2010

    • Author(s)
      Roberts DJ, et al
    • Journal Title

      J Immunother

      Volume: 33 Pages: 769-779

    • Peer Reviewed
  • [Journal Article] Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation.2010

    • Author(s)
      Yokosuka T, et al
    • Journal Title

      Immunity

      Volume: 33 Pages: 326-339

    • Peer Reviewed
  • [Journal Article] Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization.2010

    • Author(s)
      Zhou Q, et al
    • Journal Title

      J Immunol

      Volume: 185 Pages: 5082-5092

    • Peer Reviewed
  • [Journal Article] TIM-3 : A novel regulatory molecule of alloimmune activation.2010

    • Author(s)
      Boenisch O, et al
    • Journal Title

      J Immunol

      Volume: 185 Pages: 5806-5819

    • Peer Reviewed
  • [Presentation] 腫瘍免疫の基礎理論2010

    • Author(s)
      八木田秀雄
    • Organizer
      第69回日本癌学会学術総会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2010-09-24
  • [Presentation] 癌増殖における繊維素溶解系因子の役割と新規治療法の開発2010

    • Author(s)
      石原誠人
    • Organizer
      第69回日本癌学会学術総会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2010-09-24
  • [Presentation] 悪性中皮腫移植モデルに対するエピジェネティクス調節による抗IL-13受容体α2抗体の抗腫瘍増強効果2010

    • Author(s)
      竹之内信
    • Organizer
      第69回日本癌学会学術総会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2010-09-24
  • [Presentation] Function of Delta-like 1 as an adhesion molecule.2010

    • Author(s)
      Murata A
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議揚
    • Year and Date
      2010-08-27
  • [Presentation] Antibodies against B7-DC with differential binding properties exert opposite effects : Implication of dual functions in PD-1 and B7-DC interactions.2010

    • Author(s)
      Azuma M
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-26
  • [Presentation] Molecular regulation of T help for CTL.2010

    • Author(s)
      Feau S
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-26
  • [Presentation] RANKL is a critical factor for the differentiation, maintenance, and survival of antigen-sampling M cells in the intestine.2010

    • Author(s)
      Knoop KA
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-26
  • [Presentation] TNF pathway in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.2010

    • Author(s)
      Onizawa M
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-25
  • [Presentation] Premature terminal exhaustion of Friend virus-specific effector CD8 T cells by rapid induction of multiple inhibitory receptors.2010

    • Author(s)
      Takamura S
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-25
  • [Presentation] Involvement of NK-TRAIL in inter-DC antigen transfer and cross-priming after HSV infection.2010

    • Author(s)
      Kumaraguru U
    • Organizer
      第14回国際免疫学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-24

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Published: 2012-07-19  

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