Establishment of immuno-stimulatory antibody therapy against cancer

• Project/Area Number: 26290059
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Juntendo University
• Principal Investigator: YAGITA Hideo 順天堂大学, 医学部, 准教授 (30182306)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: がん / 免疫 / 抗体療法 / キラーT細胞 / CD27 / CTLA-4 / PD-1 / VISTA / 免疫賦活化 / CD40 / CD137 / IFN / DR5 / Notch / RANKL / Tim-3

Outline of Final Research Achievements

We have developed novel strategies to enhance the immunogenic cell death of cancer cells indued by anti-DR5 monoclonal antibody and to reduce its unfavorable side effect. We have also developed a novel monoclonal antibody that can directly induce unique cell death in human leukemias. We have further developed novel strategies to augment anti-tumor immunity by using antibodies activating the immunostimulatory pathways (such as CD137, CD27, and Notch2) and those blocking the immunosuppressive pathways (such as CTLA-4, PD-1, TIM-3, VISTA, and TIGIT) in combination with standard chemotherapy, radiotherapy, and antibody therapy targeting cancer cells.

Research Products

• [Int'l Joint Research] University of Queensland(Australia)
• [Int'l Joint Research] Netherlands Cancer Institute/Leiden University(オランダ)
• [Int'l Joint Research] University of Nottingham(英国)
• [Int'l Joint Research] University of Miami(米国)
• [Int'l Joint Research] Universite Libre de Bruxelles(Belgium)
• [Int'l Joint Research] Institute of Experimental Immunology(Switzerland)
• [Int'l Joint Research] University of Virginia/National Cancer Institute/Georgia Regents University(米国)
• [Int'l Joint Research] Netherlands Cancer Institute(オランダ)
• [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 Issue: 3 Pages: e0150496-e0150496
  • DOI: 10.1371/journal.pone.0150496
  • NAID: 120005838168
  • Peer Reviewed / Open Access
• [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) Issue: 12 Pages: e104-e106
  • 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) Issue: 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) Issue: 6 Pages: e1169353-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) Issue: 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, Azuma M
  • Journal Title: Oral Oncol Volume: 57 Pages: 54-60
  • DOI: 10.1016/j.oraloncology.2016.04.005
  • Peer Reviewed / Open Access
• [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) Issue: 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 Issue: 9 Pages: 1206-14
  • DOI: 10.1111/cas.13005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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) Issue: 20 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) Issue: 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) Issue: 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) Issue: 6 Pages: 1310-1321
  • DOI: 10.1158/0008-5472.can-16-2105
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Agonists of the TRAIL death receptor DR5 sensitize intestinal stem cells to chemotherapy-induced cell death and trigger gastrointestinal toxicity. (2016)
  • Author(s): Finnberg, N. K., Gokare, P., Navaraj, A., Lang Luhs K. A., Cerniglia, G., Yagita, H., Takeda, K., Motoyama, N., and EL-Deiry, W. S.
  • Journal Title: Cancer Res. Volume: 76 Issue: 3 Pages: 700-712
  • DOI: 10.1158/0008-5472.can-15-2759
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Notch ligand DLL4 defines a capability of human dendritic cells in regulating Th1 and Th17 differentiation. (2016)
  • Author(s): Meng L, Bai Z, He S, Mochizuki K, Purushe J, Sun H, Wang J, Yagita H, Mineishi S, Fung H, Yanik GA, Carcchio R, Fan X, Crisalli LM, Hexner EO, Reshef R, Zhang Y, Zhang Y
  • Journal Title: J Immunol Volume: 196 Issue: 3 Pages: 1070-1080
  • DOI: 10.4049/jimmunol.1501310
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD27 agonism plus PD-1 blockade recapitulates CD4+ T cell help in terapeutic anti-cancer vaccination. (2016)
  • Author(s): Ahrends T, Babala N, Xiao Y, Yagita H, van Eenennaam H, Borst J
  • Journal Title: Cancer Res Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells. (2015)
  • Author(s): Dhainaut M, Coquerelle C, Uzureau S, Denoeud J, Acolty V, Oldenhove G, Galuppo A, Sparwasser T, Tielemans K, Pays E, Yagita H, Borst J, Moser M
  • Journal Title: EMBO J Volume: 34 Issue: 10 Pages: 1336-1348
  • DOI: 10.15252/embj.201490312
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rational conbination of immunotherapies with clinical efficacy in mice with advanced cancer. (2015)
  • Author(s): Bransi A, Camilo Salgado O, Beffinger M, Milo K, Silina K, Yagita H, Becher B, Knuth A, van den Broek M
  • Journal Title: Cancer Immunol Res Volume: 3 Issue: 11 Pages: 1279-1288
  • DOI: 10.1158/2326-6066.cir-15-0103-t
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immunomodulatory effect of peritumorally administered interferon-beta on melanoma through tumor-associated macrophages. (2015)
  • Author(s): Kakizaki A, Fujimura T, Furudate S, Kambayashi Y, Yamauchi T, Yagita H, Aiba S
  • Journal Title: Oncoimmunology Volume: 4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD70 and IFN-1 selectively induce Eomesdermin or T-bet and synergize to promote CD8+ T-cell responses. (2015)
  • Author(s): Dong H, Franklin NA, Ritchea SB, Yagita H, Glennie MJ, Bullock TN
  • Journal Title: Eur J Immunol Volume: 45 Issue: 12 Pages: 3289-3301
  • DOI: 10.1002/eji.201445291
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bortezomib improves adoptive T cell therapy by sensitizing cancer cells to FasL cytotoxicity. (2015)
  • Author(s): Shanker A, Pellom ST, Dudimah DF, Thounaojam MC, de Kluiver RL, Brooks AD, Yagita H, McVicar DW, Murphy WJ, Longo DL, Sayers TJ
  • Journal Title: Cancer Res Volume: 75 Issue: 24 Pages: 5260-5272
  • DOI: 10.1158/0008-5472.can-15-0794
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The PTEN pathway in Treg is a critical driver of the suppressive tumor microenvironment. (2015)
  • Author(s): Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Powell JD, Yagita H, Mellor AL, Blazar BR, Munn DH
  • Journal Title: Sci Adv Volume: 1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Notch controls the persistence of autoimmune memory CD4+ T cells by maintaining glucose uptake. (2015)
  • Author(s): Maekawa Y, Ishifune C, Tsukumo S, Hozumi K, Yagita H, Yasutomo K.
  • Journal Title: Nature Medicine Volume: 21 Issue: 1 Pages: 55-61
  • DOI: 10.1038/nm.3758
  • Peer Reviewed
• [Journal Article] Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. (2015)
  • Author(s): Shindo Y, Yoshimura K, Kuramasu A, Watanabe Y, Ito H, Kondo T, Oga A, Ito H, Yoshino S, Hazama S, Tamada K, Yagita H, Oka M
  • Journal Title: Anticancer Res Volume: 35 Pages: 129-136
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. (2015)
  • Author(s): Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet A, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M
  • Journal Title: J Exp Med Volume: 212 Issue: 2 Pages: 139-148
  • DOI: 10.1084/jem.20140559
  • Peer Reviewed / Open Access
• [Journal Article] Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment. (2015)
  • Author(s): Blake SJ, Ching AL, Kenna TJ, Galea R, Large J, Yagita H, Steptoe RJ
  • Journal Title: PLoS One Volume: 10(3) Issue: 3 Pages: e0119483-e0119483
  • DOI: 10.1371/journal.pone.0119483
  • Peer Reviewed / Open Access
• [Journal Article] Piperine enhances the efficacy ofTRAIL-based therapy of triple-negative breast cancer cells. (2014)
  • Author(s): Abdelhamad S, Yokoyama S, Refaat A, Ogura K, Yagita H, Awale S, Saiki I
  • Journal Title: Anticancer Res Volume: 34 Pages: 1893-1899
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. (2014)
  • Author(s): Condamine T, Kumar V, Ramachandran IR, Youn J, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI
  • Journal Title: J Clin Invest Volume: 124 Issue: 6 Pages: 2626-2639
  • DOI: 10.1172/jci74056
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 suppresses acute myeloid leukemia development through FLT3 repression (2014)
  • Author(s): Kato T, Sakata-Yanagimoto M, Nishikii H, Miyake Y, Yokayama Y, Asabe Y, Kamada Y, Ueno M, Obara N, Suzukawa K, Hasegawa Y, Kitabayashi I, Uchida K, Hirao A, Yagita H, Kageyama R, Chiba S
  • Journal Title: Leukemia Volume: 29 Issue: 3 Pages: 576-585
  • DOI: 10.1038/leu.2014.281
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [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
• [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
• [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
• [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
• [Presentation] Combination immune checkpoint blockade with VISTA and CTLA-4 enhances anti-tumor responses. (2015)
  • Author(s): Kondo Y, Ohno T, Bhingare AC, Yagita H, Harada K, Azuma M
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Cytolytic anti-pan HLA-class II mAb and anti-pan MHC class I mAb directly induces lymphoma cell death via large pore formation. (2015)
  • Author(s): Matsuoka S, Yagita H, Ishii Y
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] VISTA and CTLA-4 combination blockade enhances multifunctionality of tumor infiltrating CD8+ T cells. (2015)
  • Author(s): Kondo Y, Ohno T, Bhingare AC, Yagita H, Harada K, Azuma M
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] The immunogenicity of antigen decides the tumoral inflammation and therapeutic efficacy of immune checkpoint blockades. (2015)
  • Author(s): Muraoka D, Seo N, Hayashi T, Harada N, Komura M, Yamaguchi R, Imoto S, Miyano S, Yagita H, Shiku H
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Effect of regulation of immune checkpoint molecules on ADCC with NK cells. (2015)
  • Author(s): Tanaka M, Terashima K, Imaida T, Abe S, Ueda S, Yagi H, Yagita H, Masuko T
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Commensal bacteria regulate thymic Aire expression (2014)
  • Author(s): Nakajima A, Negishi N, Tsurui H, Nanno M, Yagita H, Okumura K, Miyake S, Habu S
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The suppression of naive T cells requires cell-to-cell contact by TSST-1-induced anergic T cellls (2014)
  • Author(s): Negishi N, Sato T, Kametani Y, Hori S, Yagita H, Okumura K, Habu S
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Anti-tumor effects of mAb against a new immune-checkpoint molecule VISTA/PD-1H (2014)
  • Author(s): Kondo Y, Ohno T, Zhang C, Yagita H, Harada K, Azuma M
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Anti-pan MHC class I and class II mAbs directly induce lymphoma cell death via large pore formation (2014)
  • Author(s): Matsuoka S, Yagita H, Ishii Y
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] TNFR2 signaling in the epithelia may be involved in the development of colitis-associated tumor (2014)
  • Author(s): Watabe T, Nagaishi T, Suzuki M, Yamazaki M, Onizawa M, Jose N, Tokai A, Hosoya A, Totsuka M, Yagita H, Watanabe M
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Combination immunotherapy with 4-1BB mAb and PD-1 mAb enhances antitumor efficacy in mouse subcutaneous model (2014)
  • Author(s): Shindo Y, Yoshimura K, Kuramasu A, Ito H, Oga A, Maeda N, Yoshino S, Hazama S, Tamada K, Yagita H, Oka M
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Therapeutic anti-pan HLA class II mAb induces the death of leukemia/lymphoma cells via large pore formation (2014)
  • Author(s): Matsuoka S, Mizutani N, Yagita H, Hino O
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Anti-tumor effects of mAb against a new immune-checkpoint molecule VISTA (2014)
  • Author(s): Kondo Y, Ohno T, Zhang C, Yagita H, Harada K, Azuma M
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27