Development of a new immunotherapy activating both cytotoxic and helper T cells against bladder cancer

• Project/Area Number: 26293353
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Kyushu University (2015-2016); Kumamoto University (2014)
• Principal Investigator: Eto Masatoshi 九州大学, 医学(系)研究科(研究院), 教授 (90315078)
• Co-Investigator(Kenkyū-buntansha): 河野 吉昭 熊本大学, その他の研究科, 講師 (30593793)
• Co-Investigator(Renkei-kenkyūsha): NISHIMURA Yasuharu 熊本大学, 大学院生命科学研究部, 教授 (10156119)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 癌 / 免疫学 / トランスレーショナルリサーチ

Outline of Final Research Achievements

In this study, we have succeeded in identifying 4 long peptides (LPs) that comprise from 22-29 amino acids originated from Bladder cancer tumor-associated antigens (TAA). We confirmed the immunogenecity of LPs from Bladder cancer TAA (TAA-LP) by induction of TAA-LP-specific helper T (Th) cells from healthy donors. We could also detect type 1 Th (Th1) cells specific for TAA-LPs from Bladder cancer patients. Using transgenic mice expressing human HLA-A2, we next showed the induction of cytotoxic T cells (CTLs) specific for short peptides (SPs) from Bladder cancer TAA (TAA-SP), even after immunization with TAA-LPs, indicating the cross-presentation to Th cells and CTLs by TAA-LPs. We also succeeded in the enhancemant of CTLs against TAA-SPs when combined with LPs, Th clones, and anti-PD-1 mAb, implicating the new strategy of combination therapy with TAA-LPs. The above results have indicated that TAA-LPs are effective, and can be a new treatment option for patients with Bladder cancer.

Research Products

• [Journal Article] A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder. (2017)
  • Author(s): Obara W, Eto M, Mimata H, Kohri K, Mitsuhata N, Miura I, Shuin T, Miki T, Koie T, Fujimoto H, Minami K, Enomoto Y, Nasu T, Yoshida T, Fuse H, Hara I, Kawaguchi K, Arimura A, Fujioka T.
  • Journal Title: Ann Oncol Volume: 28 Issue: 4 Pages: 798-803
  • DOI: 10.1093/annonc/mdw675
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5α-Reductase Inhibitor. (2017)
  • Author(s): Shiota M, Kiyoshima K, Yokomizo A, Takeuchi A, Kashiwagi E, Dejima T, Takahashi R, Inokuchi J, Tatsugami K, Eto M.
  • Journal Title: J Urol Volume: 197 Issue: 2 Pages: 308-313
  • DOI: 10.1016/j.juro.2016.08.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Equol inhibits prostate cancer growth via degradation of the androgen receptor by Skp2. (2016)
  • Author(s): Itsumi M, Shiota M, Takeuchi A, Kashiwagi E, Inokuchi J, Tatsugami K, Kajioka S, Uchiumi T, Naito S, Eto M, Yokomizo A.
  • Journal Title: Cancer Sci Volume: in press Pages: 327-331
  • DOI: 10.1016/j.intimp.2016.03.007
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy. (2016)
  • Author(s): Wada Y, Maeda Y, Kubo T, Kikuchi K, Eto M, Imamura T
  • Journal Title: Oncol Lett Volume: 12 Pages: 3995-4000
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] n Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy. (2016)
  • Author(s): Noguchi M, Matsumoto K, Uemura H, Arai G, Eto M, Naito S, Ohyama C, Nasu Y, Tanaka M, Moriya F, Suekane S, Matsueda S, Komatsu N, Sasada T, Yamada A, Kakuma T, Itoh K.
  • Journal Title: Clin Cancer Res Volume: 22 Issue: 1 Pages: 54-60
  • DOI: 10.1158/1078-0432.ccr-15-1265
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic Significance of Preoperative Urine Cytology in Low-grade Non-muscle-invasive Bladder Cancer. (2016)
  • Author(s): Kiyoshima K, Akitake M, Shiota M, Takeuchi A, Takahashi R, Inokuchi J, Tatsugami K, Yokomizo A, Eto M.
  • Journal Title: Anticancer Res. Volume: 36 Pages: 799-802
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: Gene-environment interaction. (2016)
  • Author(s): Masaoka H, Ito H, Soga N, Hosono S, Oze I, Watanabe M, Tanaka H, Yokomizo A, Hayashi N, Eto M, Matsuo K.
  • Journal Title: Carcinogenesis Volume: Epub
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Identification of cancer-testis antigen (DEPDC1 and MPHOSPH1)-derived long peptides encompassing both CTL and HLA class II-restricted Th cell epitopes. (2016)
  • Author(s): Miki Nakane, Masatoshi Hirayama, Shohei Ueda, Mohammad Abu Sayem, Junji Yatsuda, Atsushi Irie, Satoru Senju, Masatoshi Eto, Hideki Nakayama and Yasuharu Nishimura
  • 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＆ラグナガーデンホテル
  • Year and Date: 2016-12-05
• [Presentation] Antitumor activity of recombinant BCG secreting interleukin-15-Ag85B fusion protein against bladder cancer. (2016)
  • Author(s): Takeuchi A, Shiota M, Tatsugami K, Yokomizo A, Eto 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] A randomized trial comparing two different retention periods of intravesical pirarubicin instillation for intermediate risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection. (2016)
  • Author(s): Kurahashi R, Kasejima Y, Kawano Y, Takahashi W, Yamaguchi T, Tanoue K, Sakakida H, Yatsuda J, Murakami Y, Sugiyama Y, Eto M
  • Organizer: The 111th Annual Meeting AUA 2016
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] 低リスク筋層非浸潤性膀胱癌の規定因子に関する検討． (2016)
  • Author(s): 秋武正和、清島圭二郎、塩田真己、武内在雄、高橋良輔、猪口淳一、立神勝則、横溝 晃、江藤正俊
  • Organizer: 第104回日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-04-23