Development of novel cancer immunotherapy based on comprehensive control of effector regulatory T-cells

• Project/Area Number: 26430173
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Aichi Medical University
• Principal Investigator: Suzuki Susumu 愛知医科大学, 医学部, 准教授 (70518422)
• Co-Investigator(Kenkyū-buntansha): 伊藤 旭 名古屋市立大学, 大学院医学研究科, 助教 (00571762) ; 吉川 和宏 愛知医科大学, 医学部, 教授 (60109759)
• Co-Investigator(Renkei-kenkyūsha): Ueda Ryuzo 愛知医科大学, 医学部 腫瘍免疫寄附講座, 教授 (20142169)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: エフェクター制御性T細胞 / CCケモカイン受容体4(CCR4) / 細胞傷害性T細胞 / 免疫不全マウス / 腫瘍免疫増強 / Treg / CTL / CCR4 / モガムリズマブ / FoxP3 / ＣＭＶｐｐ65

Outline of Final Research Achievements

Although elimination regulatory T-cell（Treg）by anti-CCR4 antibody was clearly observed, and the reactivation of immunity with the elimination of Tregs was partially clarified in in vitro experiment, the expected results could not be achieved because human Tregs were not almost infiltrated into cancer tissue generated in mouse. However, it is expected that the spread to mouse model for human cancer immunotherapy using immune checkpoint inhibitors etc. because human T-cells were remarkably infiltrated into the tissue and the cancer necrosis was observed. And, CCR4+Treg subset analysis in human cancer tissues was performed. it was observed that infiltration of CCR4+Treg subset is related with pathological stage and recurrence which suggest significance of cancer therapy targeting CCR4.

Research Products

• [Journal Article] がん細胞に対する抗体の現状と展望 (2016)
  • Author(s): 鈴木進、吉川和宏、上田龍三
  • Journal Title: 実験医学 Volume: 34 Pages: 122-131
• [Journal Article] モガムリズマブの新しい展開 (2016)
  • Author(s): 鈴木進、中山睿一、黒瀬浩史、上田龍三
  • Journal Title: 最新医学 Volume: 71 Pages: 126-132
  • NAID: 40020708354
• [Journal Article] Current status of immunotherapy. (2016)
  • Author(s): Suzuki S, Ishida T, Yoshikawa K and Ueda R.
  • Journal Title: Jpn J Clin Oncol Volume: 46 Issue: 3 Pages: 191-203
  • DOI: 10.1093/jjco/hyv201
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. (2015)
  • Author(s): 2.Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E.
  • Journal Title: Clin Cancer Res. Volume: 21 Issue: 19 Pages: 4327-36
  • DOI: 10.1158/1078-0432.ccr-15-0357
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic significance of tryptophan catabolism in adult T-cell leukemia/lymphoma (2015)
  • Author(s): Masaki, A., Ishida, T., Maeda, Y., Suzuki, S., Ito, A., Takino, H., Ogura, H., Totani, H., Yoshida, T., Kinoshita, S., Narita, T., Ri, M., Kusumoto, S., Inagaki, A., Komatsu, H., Niimi, A., Ueda, R., Utsunomiya, A., Inagaki, H. & Iida, S.
  • Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 21 (12) Issue: 12 Pages: 2830-2839
  • DOI: 10.1158/1078-0432.ccr-14-2275
  • NAID: 130005130183
  • Description: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma. (2015)
  • Author(s): Masaki A, Ishida T, Maeda Y, Suzuki S, Ito A, Takino H, Ogura H, Totani H, Yoshida T, Kinoshita S, Narita T, Ri M, Kusumoto S, Inagaki A, Komatsu H, Niimi A, Ueda R, Utsunomiya A, Inagaki H, Iida S.
  • Journal Title: Clin Cancer Res. Volume: -
  • NAID: 130005130183
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] モガムリズマブ (2014)
  • Author(s): 鈴木 進, 石田 高司, 吉川 和宏, 上田 龍三
  • Journal Title: The Frontiers in Life Sciences. 生命科学から創薬へのイノベーション Volume: 1 Pages: 183-195
• [Presentation] CDK9 as target for treatment in EBV associated T- and NK-cell lymphoproliferative diseases. (2016)
  • Author(s): Kinoshita S, Ishida T, Narita T, Itou A, Masaki A, Suzuki S, Ri M, Kusumoto S, Komatsu H, Kuroda T, Inagaki H, Abe Y, Ueda R and Iida S.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Prognostic significance of tryptophan catabolism in newly diagnosed Hodgkin Lymphoma. (2016)
  • Author(s): Masaki A, Ishida T, Narita T, Itou A, Suzuki S, Kusumoto S, Komatsu H, Ilseung C, Suehiro Y, Abe Y, Inagaki H, Ueda R and Iida S.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Indoleamine 2,3-dioxygenase 1 as a novel molecular target in adult T-cell leukemia/lymphoma. (2016)
  • Author(s): Ishida T, Ito A,Masaki A, Saito M, Urakawa I, Ishii T, Suzuki S, Kusumoto S, Komatsu H, Inagaki H, Iida S, Takahashi T and Ueda R.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] 5-FU (fluorouracil) sensitizes oral squamous cell carcinoma (OSCC) to cytotoxic T-lymphocyte (CTL). (2016)
  • Author(s): Suzuki S, Nishio M, Ohmura Y, Yoshikawa K, Kazaoka Y and Ueda R.
  • Organizer: 第75回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] CDK9 as target for treatment in EBV associated T- and NK-cell lymphoproliferative diseases. (2016)
  • Author(s): Kinoshita S, Ishida T, Narita T, Itou A, Masaki A, Suzuki S, Ri M, Kusumoto S, Komatsu H, Kuroda T, Inagaki H, Abe Y, Ueda R and Iida S.
  • Organizer: 第75回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Prognostic significance of tryptophan catabolism in newly diagnosed Hodgkin Lymphoma. (2016)
  • Author(s): Masaki A, Ishida T, Narita T, Itou A, Suzuki S, Kusumoto S, Komatsu H, Ilseung C, Suehiro Y, Abe Y, Inagaki H, Ueda R and Iida S.
  • Organizer: 第75回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Indoleamine 2,3-dioxygenase 1 as a novel molecular target in adult T-cell leukemia/lymphoma. (2016)
  • Author(s): Ishida T, Ito A,Masaki A, Saito M, Urakawa I, Ishii T, Suzuki S, Kusumoto S, Komatsu H, Inagaki H, Iida S, Takahashi T and Ueda R.
  • Organizer: 第75回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] C-C chemokine receptor 4 positive regulatory T cells increased in biopsy specimens of poorly prognostic prostate cancer. (2016)
  • Author(s): Watanabe M, Kanao K, Suzuki S, Nakamura K, Yoshikawa K, Ueda R, and Sumitomo M. C-C chemokine receptor 4 positive regulatory T cells increased in biopsy specimens of poorly prognostic prostate cancer.
  • Organizer: 第75回 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Indoleamine 2,3-dioxygenase 1 as a novel molecular target in adult T-cell leukemia/lymphoma. (2015)
  • Author(s): Masaki A, Ishida T, Meda Y, Suzuki S, Ito A, Ogura H, Narita T, Totani H, Kinoshita S, Yoshida T, Ri M, Kusumoto S, Komatsu H, Ueda R, Inagaki H and Iida S.
  • Organizer: 第77回 日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Potential treatment of adult T-cell leukemia/lymphoma by a novel P-TEFb/CDK9 inhibitor BAY1143572 (2015)
  • Author(s): Narita T, Ishida T, Ito A, Masaki A, Suzuki S, Takino H, Ogura H, Yoshida T, Ri M, Kusumoto S, Komatsu H, Imada K, Takaori KA, Inagaki H, Arne S, Stuart I, Ueda R, and Iida S.
  • Organizer: 第77回 日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Immunotherapy for solid tumors based on regulation of regulatory T lymphocyte. (2015)
  • Author(s): Suzuki S, Ishida T, Kurose K, Ohue Y, Nishikawa H, Iida S, Wada H, Oka M, Nakayama E and Ueda R.
  • Organizer: 第74回 日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients (2015)
  • Author(s): Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Suzuki S, Kakimi K, Nishikawa H, Ueda R, Oka M, Nakayama E.
  • Organizer: 第74回 日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Indoleamine 2,3-dioxygenase 1 as a novel molecular target in adult T-cell leukemia/lymphoma. (2015)
  • Author(s): Masaki A, Ishida T, Suzuki S, Ito A, Narita T, Ri M, Kusumoto S, Komatsu H, Ueda R, Inagaki H, Iida S.
  • Organizer: 第74回 日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. (2015)
  • Author(s): Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R and Nakayama E.
  • Organizer: 第19回日本がん免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-09
• [Presentation] Chemo-immunotherapy with CTL and 5-fluorouracil (5FU) for head and neck squamous cell carcinoma (HNSCC). (2014)
  • Author(s): Nishio-Nagai M, Suzuki S, Hayashi T, Ohmura Y, Yamada Y, Yoshikawa K, Ueda R and Kazaoka Y.
  • Organizer: 22nd Annual International Cancer Immunotherapy Symposium.
  • Place of Presentation: ニューヨーク
  • Year and Date: 2014-10-05
• [Presentation] 口頸部扁平上皮癌（HNSCC）における5-フルオロウラシル(５－FU）併用免疫療法. (2014)
  • Author(s): 西尾麻矢子、鈴木 進、大村元伸、山田陽一、上田龍三、吉川和宏、風岡宜暁
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-27
• [Presentation] CCR4を標的抗原とする、新規がん免疫療法. (2014)
  • Author(s): 石田高司、鈴木 進、上田龍三
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26
• [Presentation] 制御性T細胞解析方法の標準化に向けた多施設共同研究 (2014)
  • Author(s): 長瀬博次、和田 尚、西川博嘉、鈴木 進、平家勇司、小嶋隆嗣、垣見和宏、舩越 建、飯田真介、石田高司、佐藤永一、鵜殿平一郎、岡三喜男、中山睿一、土岐祐一郎、上田龍三
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 2014-07-31
• [Presentation] 成人T細胞性白血病/リンパ腫におけるindoleamine 2,3-dioxygenaseの臨床的意義. (2014)
  • Author(s): 正木彩子、石田高司、前田康博、稲垣淳、鈴木進、伊藤旭、成田朋子、榊原健夫、滝野寿、李政樹、楠本茂、小松弘和、上田龍三、稲垣宏、宇都宮與、飯田真介
  • Organizer: 第54回日本リンパ網内系学会総会
  • Place of Presentation: 山形
  • Year and Date: 2014-06-21
• [Book] 最新医学 (2016)
  • Author(s): 鈴木進、中山睿一、黒瀬浩史、上田龍三 モガムリズマブの新しい展開
  • Total Pages: 7
  • Publisher: 最新医学社
• [Book] 臨床血液 (2015)
  • Author(s): 正木彩子, 石田高司、 前田 康弘、 鈴木進、上田龍三、飯田真介
  • Total Pages: 10
  • Publisher: 臨床血液学会
• [Book] Progress in clinical use of CCR4 antibody for regulatory T cell suppression. Inflammation and Immunity in Cancer. (2015)
  • Author(s): Suzuki S, Ishida T, Yoshikawa K, Ueda R.
  • Total Pages: 11
  • Publisher: Springer
• [Book] Clinical application of anti-CCR4 monoclonal antibody. Recent advances in cancer immunotherapy (2014)
  • Author(s): Ueda R, Suzuki S, Yoshikawa K, Ishida T.
  • Total Pages: 6
  • Publisher: Princess Takamatsu Cancer Research Fund