Establishment of immuno-stimulatory antibody therapy against cancer

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26290059
• Research Institution: Juntendo University
• Principal Investigator: 八木田 秀雄 順天堂大学, 医学部, 准教授 (30182306)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 抗体療法 / 免疫賦活化 / CD27 / CD40 / PD-1 / CTLA-4 / CD137 / VISTA

Outline of Annual Research Achievements

(1) ホジキンリンパ腫や成人T細胞白血病 (ATL) 細胞を直接的に傷害するpan-MHCII抗体を樹立した。(2) B16マウスメラノーマモデルにおいて、抗CTLA-4抗体と抗RANKL抗体の組み合わせによって、相乗的に肺転移が抑制されることを示した。(3) HPV発現マウス腫瘍モデルにおいて、CTLエピトープのDNAワクチン効果を、CD27に対するアゴニスト抗体とPD-1に対する阻害抗体との組み合わせによって、CD4陽性ヘルパーT細胞非依存性に増強しうることを示した。(4) 新規チェックポイント分子VISTAに対する阻害抗体を樹立し、VISTAとCTLA-4のコンビネーション阻害によって相乗的な抗腫瘍効果が得られることを示した。(5) ヒトIgG1のCDR領域にTRP-2やgp100あるいはNY-ESO-1エピトープを導入したDNAワクチンの抗腫瘍効果が抗PD-1抗体との併用で著しく増強されることを示した。(6) PTEN欠損BRAFV600変異マウスメラノーマモデルにおいて、PD-1阻害抗体とCD137アゴニスト抗体の組み合わせによって放射線療法の効果が相乗的に増強されることを示した。(7) IL-17Aを産生して炎症性の腫瘍増大に関与するgamma/delta T細胞がCD30を高発現しており、CD30リガンドに対する阻害抗体が抗腫瘍効果を示すことを見出した。(8) 抗PD-1抗体耐性のマウス腫瘍モデルにおいて、CD40アゴニスト抗体との併用によってIL-12依存性に抗PD-1抗体の効果が増強されることを示した。(9) 放射線照射後の腫瘍内で産生されるVEGFを標的として、VEGF特異的なアプタマーとCD137特異的なアプタマーとの複合体によって、全身的なCD137アゴニスト抗体やPD-1/CTLA-4阻害抗体の投与よりも強い抗腫瘍効果が得られることを示した。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Causes of Carryover

28年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

28年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Queensland(Australia)
  • Country Name: Australia
  • Counterpart Institution: University of Queensland
• [Int'l Joint Research] Netherlands Cancer Institute/Leiden University(オランダ)
  • Country Name: NETHERLANDS
  • Counterpart Institution: Netherlands Cancer Institute/Leiden University
• [Int'l Joint Research] University of Nottingham(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Nottingham
• [Int'l Joint Research] University of Miami(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of Miami
• [Journal Article] Establishment of a therapeutic anti-pan HLA-class II monoclonal antibody that directly induces lymphoma cell death via large pore formation. (2016)
  • Author(s): Matsuoka S, Ishii Y, Nakao A, Abe M, Ohtsuji N, Momose S, Jin H, Arase H, Sugimoto K, Nakauchi Y, Masutani H, Maeda M, Yagita H, Komatsu N, Hino O
  • Journal Title: PLoS One Volume: 11(3) Pages: e0150496
  • DOI: 10.1371/journal.pone.0150496
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination anti-CTLA-4 and anti-RANKL in metastatic melanoma. (2016)
  • Author(s): Smyth MJ, Yagita H, McArthur GA
  • Journal Title: J Clin Oncol Volume: 34(12) Pages: e104-106
  • DOI: 10.1200/JCO.2013.51.3572
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD27 agonism plus PD-1 blockade recapitulates CD4+ T cell help in therapeutic anti-cancer vaccination. (2016)
  • Author(s): Ahrends T, Babala N, Xiao Y, Yagita H, van Eenennaam H, Borst J
  • Journal Title: Cancer Res Volume: 76(10) Pages: 2921-2931
  • DOI: 10.1158/0008-5472.CAN-15-3130
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhaned by checkpoit blockade. (2016)
  • Author(s): Xue W, Metheringham RL, Brentville VA, Gunn B, Symonds P, Yagita H, Ramage JM, Durrant LG
  • Journal Title: Oncoimmunology Volume: 5(6) Pages: e1169353
  • DOI: 10.1080/2162402X.2016.1169353
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma. (2016)
  • Author(s): Kroon P, Gadiot J, Peeters M, Gasparini A, Deken MA, Yagita H, Verheij M, Borst J, Blank CU, Verbrugge I
  • Journal Title: Cancer Immunol Immunother Volume: 65(6) Pages: 753-763
  • DOI: 10.1007/s00262-016-1843-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. (2016)
  • Author(s): Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M
  • Journal Title: Oral Oncol Volume: 57 Pages: 54-60
  • DOI: 10.1016/j.oraloncology.2016.04.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Systemic DC activation modulates the tumor microenvironment and shapes the long-lived tumor-specific memory mediated by CD8+ T cells. (2016)
  • Author(s): Shimizu K, Yamasaki S, Shinga J, Sato Y, Watanabe T, Ohara O, Kuzushima K, Yagita H, Komuro Y, Asakura M, Fujii S
  • Journal Title: Cancer Res Volume: 76(13) Pages: 3756-3766
  • DOI: 10.1158/0008-5472.CAN-15-3219
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IL-17A-producing CD30+ Vδ1 T cells drive inflammation-induced cancer progression. (2016)
  • Author(s): Kimura Y, Nagai N, Tsunekawa N, Sato-Matsushita M, Yoshimoto T, Cua DJ, Iwakura Y, Yagita H, Okada F, Tahara H, Saiki I, Irimura T, Hayakawa Y
  • Journal Title: Cancer Sci Volume: 107(9) Pages: 1206-1214
  • DOI: 10.1111/cas.13005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells. (2016)
  • Author(s): Beyranvand Nejad E, van der Sluis TC, van Duikeren S, Yagita H, Janssen GM, van Veelen PA, Melief CJ, van der Burg SH, Arens R
  • Journal Title: Cancer Res Volume: 76(29) Pages: 6017-6029
  • DOI: 10.1158/0008-5472.CAN-16-0881
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Agonistic CD40 mAb-driven IL-12 reverses resistance to anti-PD1 in a T cell-rich tumor. (2016)
  • Author(s): Ngiow SF, Young A, Blake SJ, Hill GR, Yagita H, Teng MW, Korman AJ, Smyth MJ
  • Journal Title: Cancer Res Volume: 76(21) Pages: 6266-6277
  • DOI: 10.1158/0008-5472.CAN-16-2141
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. (2016)
  • Author(s): Xue W, Brentville VA, Symonds P, Cook KW, Yagita H, Metheringham RL, Durrant LG
  • Journal Title: Oncotarget Volume: 7(50) Pages: 83088-83100
  • DOI: 10.18632/oncotarget.13070
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radiation-induced enhancement of antitumor T cell immunity by VEGF-targeted 4-1BB costimulation. (2016)
  • Author(s): Schrand B, Verma B, Levay A, Patel S, Castro I, Benaduce AP, Brenneman R, Umland O, Yagita H, Gilboa E, Ishkanian AS
  • Journal Title: Cancer Res Volume: 77(6) Pages: 1310-1321
  • DOI: 10.1158/0008-5472.CAN-16-2105
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Non-apoptotic, non-necrotic novel cell death (anapocosis) of lymphoma cells induced by therapeutic mAbs. (2016)
  • Author(s): Matsuoka S, Ishii Y, Yagita H
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05 – 2016-12-07
• [Presentation] Antigen delivery to tumoral macrophages leads to eradication of tumor resistant to immune checkpoint inhibitors. (2016)
  • Author(s): Muraoka D, Seo N, Harada N, Fujii K, Komuro M, Imoto S, Yamaguchi R, Miyano S, Yagita H, Akiyoshi K, Shiku H
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06 – 2016-10-08
• [Presentation] A combination of anti-angiogenic and anti-lymphangiogenic therapies augments effects of an antitumor immunotherapy. (2016)
  • Author(s): Tsukita Y, Okazaki T, Yagita H, Ichinose M
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06 – 2016-10-08
• [Presentation] Anti-pan MHC mAb induce cell death for ex-vivo lymphoma cells by anapocosis. (2016)
  • Author(s): Matsuoka S, Ishii Y, Takamatsu H, Hasegawa H, Mizutani N, Yagita H, Hino O
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06 – 2016-10-08
• [Presentation] Augmented anti-cancer therapeutic effect using antibodies to multiple target molecules with immune checkpoint blockade. (2016)
  • Author(s): Terashima K, Tanaka M, Imaida T, Ueda S, Yagita H, Masuko T
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06 – 2016-10-08