The development of a comprehensive immunotherapy based on anti-CCR4 antibody for hematological malignancies

• Project/Area Number: 22689029
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: ISHIDA Takashi 名古屋市立大学, 大学院・医学研究科, 准教授 (80405183)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥21,970,000 (Direct Cost: ¥16,900,000、Indirect Cost: ¥5,070,000); Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2011: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2010: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: CCR4 / CCR4 抗体 / 制御性 T 細胞 / CTL / ATL / NOG マウス / ポテリジオ / 制御性T細胞 / HTLV-1 / Tax / Mogamulizumab / がん・精巣抗原 / KW-0761 / NOGマウス

Research Abstract

1． Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma (ATL)
2． Cancer Testis antigens are potential molecular targets for immunotherapy of ATL.
3． Allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL.
4． KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile.
5． The reduction of Treg cells by mogamulizumab in cancer patients would have bothpotential benefits leading to enhanced antitumor immunity, but also pose risks of autoimmune disease.

Research Products

• [Journal Article] Successful salvage therapy using lenalidomide in a patient with relapsed multiple myeloma after allogeneic hematopoietic stem cell transplantation (2013)
  • Author(s): Suzuki T, Kusumoto S, Yoshida T, Mori F, Ito A, Ri M, Ishida T, Komatsu H, Niimi A, Iida S
  • Journal Title: Int J Hematol
  • NAID: 10031168524
• [Journal Article] Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia / lymphoma. (2013)
  • Author(s): Ishida T
  • Journal Title: Cancer Sci. Volume: 104 Issue: 5 Pages: 647-50
  • DOI: 10.1111/cas.12116
  • Peer Reviewed
• [Journal Article] Angioimmunoblastic T-cell lymphoma mice model. (2013)
  • Author(s): Sato F ,Ishida T, Ito A, Mori F, Masaki A, Takino H, Narita T, Ri M, Kusumoto S, Suzuki S, Komatsu H, Niimi A, Ueda R, Inagaki H, Iida S.
  • Journal Title: Leuk Res Volume: 37 Pages: 21-7
• [Journal Article] Bath-PUVA Therapy Decreases Infiltrating CCR4-Expressing Tumor Cells and Regulatory T Cells in Patients With Mycosis Fungoides. (2013)
  • Author(s): Kato H
  • Journal Title: Clin Lymphoma Myeloma Leuk. Volume: Epub ahead Issue: 3 Pages: 273-280
  • DOI: 10.1016/j.clml.2012.12.002
  • Peer Reviewed
• [Journal Article] Angioimmunoblastic T-cell lymphoma mice model. (2013)
  • Author(s): Sato F
  • Journal Title: Leuk Res. Volume: 37 Issue: 1 Pages: 21-7
  • DOI: 10.1016/j.leukres.2012.09.009
  • Peer Reviewed
• [Journal Article] Reactivation of hepatitis B virus in a patient with adult T-cell leukemia/lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab. (2013)
  • Author(s): Nakano N
  • Journal Title: Hepatol Res. Volume: Epub ahead Issue: 3 Pages: 354-357
  • DOI: 10.1111/hepr.12117
  • Peer Reviewed
• [Journal Article] Successful salvage therapy using lenalidomide in a patient with relapsed multiple myeloma after allogeneic hematopoietic stem cell transplantation. (2013)
  • Author(s): Suzuki T, Kusumoto S, Yoshida T, Mori F, Ito A, Ri M, Ishida T, Komatsu H, Niimi A, Iida S.
  • Journal Title: Int J Hematol Volume: in press Issue: 4 Pages: 540-543
  • DOI: 10.1007/s12185-013-1301-4
  • NAID: 10031168524
  • Peer Reviewed
• [Journal Article] Tax is a potential molecular target for immunotherapy of adult T -cell leukemia/lymphoma (2012)
  • Author(s): Suzuki S, Masaki A, Ishida T, Ito A, Mori F, Sato F, Narita T, Ri M, Kusumoto S, Komatsu H, Fukumori Y, Nishikawa H, Tanaka Y, Niimi A, Inagaki H, Iida S, Ueda R
  • Journal Title: Cancer Sci Volume: 103 Pages: 1764-73
• [Journal Article] Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukemia-Lymphoma: A Multicenter Phase II Study (2012)
  • Author(s): Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, Saburi Y, Miyamoto T, Takemoto S, Suzushima H, Tsukasaki K, Nosaka K, Fujiwara H, Ishitsuka K, Inagaki H, Ogura M, Akinaga S, Tomonaga M, Tobinai K, Ueda R.
  • Journal Title: J Clin Oncol Volume: 30 Pages: 837-42
• [Journal Article] Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma (2012)
  • Author(s): *Nishikawa H, *Maeda Y, *Ishida T, Gnjatic S, Sato E, Mori F, Sugiyama D, Ito A, Fukumori Y, Utsunomiya A, Inagaki H, Old LJ, Ueda R, Sakaguchi S.
  • Journal Title: Blood Volume: 119 Pages: 3097-104
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for adult T -cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study (2012)
  • Author(s): Ishida T, Hishizawa M, Kato K, Tanosaki R, Fukuda T, Taniguchi S, Eto T, Takatsuka Y, Miyazaki Y, Moriuchi Y, Hidaka M, Akashi K, Uike N, Sakamaki H, Morishima Y, Kato K, Suzuki R, Nishiyama T, Utsunomiya A
  • Journal Title: Blood Volume: 120(8) Pages: 1734-41
• [Journal Article] Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. (2012)
  • Author(s): Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S
  • Journal Title: Blood Cancer J Volume: 2(7)
• [Journal Article] Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model. (2012)
  • Author(s): Mori F, Ishida T, Ito A, Sato F, Masaki A, Takino H, Ri M, Kusumoto S, Komatsu H, Ueda R, Inagaki H, Iida S.
  • Journal Title: Blood Cancer J Volume: 2(4)
• [Journal Article] Forkhead box P1 overexpression and its clinicopathologic significance in peripheral T-cell lymphoma, not otherwise specified. (2012)
  • Author(s): Yamada S, Sato F, Xia H, Takino H, Kominato S, Ri M, Ishida T, Iida S, Inagaki H, Yamada K.
  • Journal Title: Hum Pathol Volume: 43 Pages: 1322-7
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study. (2012)
  • Author(s): Ishida T
  • Journal Title: Blood Volume: 120 Issue: 8 Pages: 1734-41
  • DOI: 10.1182/blood-2012-03-414490
  • Peer Reviewed
• [Journal Article] Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma. (2012)
  • Author(s): Suzuki S
  • Journal Title: Cancer Sci. Volume: 103 Issue: 10 Pages: 1764-73
  • DOI: 10.1111/j.1349-7006.2012.02371.x
  • Peer Reviewed
• [Journal Article] Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. (2012)
  • Author(s): Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S.
  • Journal Title: Blood Cancer J. Volume: 2 Issue: 7 Pages: e79-e79
  • DOI: 10.1038/bcj.2012.26
  • Peer Reviewed
• [Journal Article] Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma a multicenter phase II study (2012)
  • Author(s): Ishida T.
  • Journal Title: J Clin Oncol Volume: 30(8) Issue: 8 Pages: 837-42
  • DOI: 10.1200/jco.2011.37.3472
  • Peer Reviewed
• [Journal Article] Cancer/testis antigens are novel targets of immunotherapy for adult T cell leukemia/lymphoma (2012)
  • Author(s): Nishikawa H.
  • Journal Title: Blood Volume: 119(13) Issue: 13 Pages: 3097-104
  • DOI: 10.1182/blood-2011-09-379982
  • Peer Reviewed
• [Journal Article] Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model (2012)
  • Author(s): Mori F, Ishida T, Ito A, Sato F, Masaki A, Takino H, Ri M, Kusumoto S, Komatsu H, Ueda R, Inagaki H, Iida S.(corresponding author)
  • Journal Title: Blood Cancer Journal Volume: (in press)
  • Peer Reviewed
• [Journal Article] Immunopathogenesis of lymphoma: Focus on CCR4 (2011)
  • Author(s): Ishida T, Ueda R
  • Journal Title: Cancer Sci Volume: 102 Pages: 44-50
  • NAID: 10029288284
• [Journal Article] Antibody therapy for Adult T-cell leukemia-lymphoma (2011)
  • Author(s): Ishida T, Ueda R
  • Journal Title: Int J Hematol Volume: 94(5) Pages: 443-452
  • NAID: 10030265658
• [Journal Article] Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with Relapsed/Refractory Multiple Myeloma (2011)
  • Author(s): Shimizu K, Murakami H, Sawamura M, Hattori Y, Okamoto S, Miwa A, Sugiura I, Shimazaki C, Taniwaki M, Ishida T, Hayashi T, Kosugi H, Yuge M, Iida S, Ishida T, Sunami K, Asaoku H, Sakai A, Abe M, Takagi T
  • Journal Title: International Journal of Clinical Medicine Volume: 2 Pages: 570-575
• [Journal Article] Antibody therapy for Adult T-cell leukemia-lymphoma (2011)
  • Author(s): Ishida T, Ueda R.(corresponding author)
  • Journal Title: Int J Hematol Volume: 94 Issue: 5 Pages: 443-452
  • DOI: 10.1007/s12185-011-0941-5
  • NAID: 10030265658
  • Peer Reviewed
• [Journal Article] Immunopathogenesis of lymphoma : Focus on CCR4. 2011 : 102 : 44-50 (2011)
  • Author(s): Ishida T, Ueda R.(corresponding author)
  • Journal Title: Cancer Sci Volume: 102 Pages: 44-50
  • Peer Reviewed
• [Journal Article] Forkhead box P1 overexpression and its clinicopathological significance in peripheral T-cell lymphoma, not otherwise specified (2011)
  • Author(s): Yamada S, Sato F, Xia H, Takino H, Kominato S, Ri M, Ishida T, Iida S, Inagaki H, Yamada K.
  • Journal Title: Hum Pathol Volume: 2 Issue: 8 Pages: 570-575
  • DOI: 10.1016/j.humpath.2011.10.013
  • Peer Reviewed
• [Journal Article] A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγ(null) mouse lymphoma model. (2010)
  • Author(s): Sato F, Ito A, Ishida T, Mori F, Takino H, Inagaki A, Ri M, Kusumoto S, Komatsu H, Iida S, Okada N, Inagaki H, Ueda R.
  • Journal Title: Cancer Immunol Immunother Volume: 59 Pages: 1791-800
• [Journal Article] Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress (2010)
  • Author(s): Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, Inagaki A, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R
  • Journal Title: Leukemia Volume: 24 Pages: 1506-12
• [Journal Article] Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma: two case reports (2010)
  • Author(s): Yoshida T, Kusumoto S, Inagaki A, Mori F, Ito A, Ri M, Ishida T, Komatsu H, Iida S, Sugauchi F, Tanaka Y, Mizokami M, Ueda R
  • Journal Title: Int J Hematol. Volume: 91 Pages: 844-9
  • NAID: 10026511317
• [Journal Article] Defucosylated humanized anti -CCR4 monoclonal antibody KW-0761 as a novelimmunotherapeutic agent for adult T-cell leukemia/lymphoma (ATLL) (2010)
  • Author(s): Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, Iida S, Imada K, Uchiyama T, Akinaga S, Shitara K, Ueda R.
  • Journal Title: Clin Cancer Res Volume: 16 Pages: 1520-1531
• [Journal Article] Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients with Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma (2010)
  • Author(s): Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y. Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T, Matsushima K, Akinaga S, Ogura M, Tomonaga M, Ueda R
  • Journal Title: J Clin Oncol Volume: 28 Pages: 1591-8
• [Journal Article] A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγ (null) mouse lymphoma model. (2010)
  • Author(s): Sato F, Ito A, Ishida T, Mori F, Takino H, Inagaki A, Ri M, Kusumoto S, Komatsu H, Iida S, Okada N, Inagaki H, Ueda R.
  • Journal Title: Cancer Immunol Immunother Volume: 59 Pages: 1791-1800
  • Peer Reviewed
• [Journal Article] Bortezomib-resistant myeloma cell lines : a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. (2010)
  • Author(s): Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, Inagaki A, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R.
  • Journal Title: Leukemia. Volume: 24 Pages: 1506-1512
  • Peer Reviewed
• [Journal Article] Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma : two case reports. (2010)
  • Author(s): Yoshida T, Kusumoto S, Inagaki A, Mori F, Ito A, Ri M, Ishida T, Komatsu H, Iida S, Sugauchi F, Tanaka Y, Mizokami M, Ueda R.
  • Journal Title: Int J Hematol. Volume: 91 Pages: 844-849
  • NAID: 10026511317
  • Peer Reviewed
• [Journal Article] Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma (ATLL). (2010)
  • Author(s): Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, Iida S, Imada K, Uchiyama T, Akinaga S, Shitara K, Ueda R.
  • Journal Title: Clin Cancer Res. Volume: 16 Pages: 1520-1531
  • Peer Reviewed
• [Journal Article] Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients with Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma. (2010)
  • Author(s): Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y.Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T, Matsushima K, Akinaga S, Ogura M, Tomonaga M, Ueda R.
  • Journal Title: J Clin Oncol. Volume: 28 Pages: 1591-1598
  • Peer Reviewed
• [Journal Article] Utsunomiya A. Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab
  • Author(s): Nakano N, Kusumoto S, Tanaka Y, IshidaT, Takeuchi S, Takatsuka Y, Akinaga S, Mizokami M, Ueda R
  • Journal Title: Hepatol Res Volume: (in press)
• [Presentation] Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CCR4 Antibody, in Patients with Relapsed Peripheral and Cutaneous T-Cell Lymphoma(oral presentation) (2012)
  • Author(s): Ishida T, Ogura M, MD, Hatake K,et al
  • Organizer: 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA, USA
• [Presentation] Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CCR4 Antibody, in Patients with Relapsed Peripheral and Cutaneous T-Cell Lymphoma (oral presentation) (2012)
  • Author(s): Ishida T, Ogura M, MD, Hatake K, et al.
  • Organizer: 54th ASH Annual Meeting and Exposition (oral presentation)
  • Place of Presentation: Atlanta, GA
• [Presentation] Development of the CCR4-targeted mAb therapy for Adult T-cell leukemia/lymphoma (ATL), Symposium 10 HTLV-1/ATL (2011)
  • Author(s): Takashi Ishida
  • Organizer: The XXV Symposium of the International Association for Comparative Research on Leukemia and Related Disease
  • Place of Presentation: 東京大学(東京)(招待講演)
• [Presentation] Promising Results of An Anti-CCR4 Antibody, KW-0761, for Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) (2011)
  • Author(s): K.Tobinai, T.Ishida, K.Yamamoto, N.Uike, K.Tsukasaki, A.Utsunomiya, K.Uozumi, M.Tomonaga, R.Ueda
  • Organizer: 11th International. Conference on. Malignant Lymphoma
  • Place of Presentation: Palazzo dei Congressi(スイス)
• [Presentation] Promising results of an anti-CCR4 antibody, KW-0761, for relapsed Adult T-Cell Leukemia-Lymphoma (ATL) (2011)
  • Author(s): Atae Utsunomiya, Kensei Tobinai, Kazuhito Yamamoto, Takashi Ishida, Naokuni Uike, Kunihiro Tsukasaki, Kimiharu Uozumi, Masao Tomonaga, Ryuzo Ueda
  • Organizer: 15th International Conference on Human Retroviruses : HTLV and Related Viruses
  • Place of Presentation: aula Pieter De Somer(ベルギー)
• [Presentation] Multicenter Phase II Study of KW-0761, a Defucosylated Anti-CCR4 Antibody, In Relapsed Patients with Adult T-Cell Leukemia-Lymphoma (ATL)(oral presentation) (2010)
  • Author(s): Ishida T, Joh T, Uike N,et al.
  • Organizer: 52th ASH Annual Meeting And Exposition
  • Place of Presentation: ORLAND, FL, USA
  • Year and Date: 2010-12-06
• [Presentation] Multicenter Phase II Study of KW-0761, a Defucosylated Anti-CCR4 Antibody, In Relapsed Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (2010)
  • Author(s): Takashi Ishida, Tatsuro Joh, Naokuni Uike, Kazuhito Yamamoto, Atae Utsunomiya, Shinichiro Yoshida, Yoshio Saburi, Toshihiro Miyamoto, Shigeki Takemoto, Hitoshi Suzushima, Kunihiro Tsukasaki, Kisato Nosaka, Hiroshi Fujiwara, Kenji Ishitsuka, Hiroshi Inagaki, Michinori Ogura, Shiro Akinaga, Masao Tomonaga, Kensei Tobinai, Ryuzo Ueda.
  • Organizer: 52th Annual Meeting And Exposition
  • Place of Presentation: ORLAND, FL(米国)
  • Year and Date: 2010-12-06