The development of novel treatment strategies for ATL patients by mogamulizumab

• Project/Area Number: 25290058
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Nagoya City University
• Principal Investigator: ISHIDA TAKASHI 名古屋市立大学, 医学(系)研究科(研究院), 准教授 (80405183)
• Co-Investigator(Kenkyū-buntansha): UEDA Ryuzo 愛知医科大学, 医学部, 教授 (20142169)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: CCR4 / 制御性T細胞 / 成人T細胞白血病/リンパ腫 / IDO / mogamulizumab / 成人T細胞白血病リンパ腫 / ATL / HTLV-1 / Tax

Outline of Final Research Achievements

The multicenter prospective clinical observational study (MIMOGA study, UMIN000008696) is currently ongoing (as of April 2016). The interim analysis of 49 patients enrolled in this study demonstrated that skin-related AEs of grades 2-4 were observed in 7 patients (14.3%), but they had a trend towards prolonged OS (median OS, not reached vs 13.2 months), relative to patients with no or grade 1-2 skin-related AEs.　The analysis also demonstrated that ATL cells of effector Treg phenotype (CD45RA-FOXP3high, n=17) had a prolonged OS compared to the others (n=27) (median OS, not reached vs 12.8 months).
ATL cells and/or cells of the tumor microenvironment are likely to produce IDO, which would lead to a high Kyn/Trp ratio and a high Kyn level not only in the tumor microenvironment, but also in the blood. A high serum Kyn/Trp ratio was an independent significant detrimental prognostic factors in ATL patients. IDO is an attractive target for novel anti-ATL agents, combined with mogamulizumab.

Research Products

• [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] 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] Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. (2015)
  • Author(s): Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R
  • Journal Title: Br J Haematol Volume: 未定 Issue: 5 Pages: 672-682
  • DOI: 10.1111/bjh.13338
  • Peer Reviewed
• [Journal Article] A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma. (2015)
  • Author(s): Ishitsuka K, Utsunomiya A, Katsuya H, Takeuchi S, Takatsuka Y, Hidaka M, Sakai T, Yoshimitsu M, Ishida T, Tamura K.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 9 Pages: 1219-1223
  • DOI: 10.1111/cas.12735
  • Peer Reviewed
• [Journal Article] Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy. (2015)
  • Author(s): Narita T, Ri M, Masaki A, Mori F, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S.
  • Journal Title: Blood Cancer J. Volume: 5 Issue: 12 Pages: e373-e373
  • DOI: 10.1038/bcj.2015.98
  • Peer Reviewed
• [Journal Article] Screening Performance for Frailty Among Older Patients With Cancer: A Cross-Sectional Observational Study of Two Approaches. (2015)
  • Author(s): Okuyama T, Sugano K, Iida S, Ishida T, Kusumoto S, Akechi T.
  • Journal Title: J Natl Compr Canc Netw. Volume: 13 Pages: 1525-1531
  • Peer Reviewed
• [Journal Article] Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians. (2015)
  • Author(s): Sugano K, Okuyama T, Iida S, Komatsu H, Ishida T, Kusumoto S, Uchida M, Nakaguchi T, Kubota Y, Ito Y, Takahashi K, Akechi T.
  • Journal Title: PLoS One. Volume: 10
  • Peer Reviewed
• [Journal Article] Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians. (2015)
  • Author(s): Sugano, K., T. Okuyama, S. Iida, H. Komatsu, T. Ishida, S. Kusumoto, M. Uchida, T. Nakaguchi, Y. Kubota, Y. Ito, K. Takahashi, and T. Akechi
  • Journal Title: PLoS One Volume: 10(8) Issue: 8 Pages: 398-404
  • DOI: 10.1371/journal.pone.0136163
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy (2015)
  • Author(s): Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito A, Ri M, Komatsu H, Murakami S, Mizokami M, Ueda R, Niimi A, Inagaki H, Tanaka Y, Iida S.
  • Journal Title: International Journal of Hematology Volume: 印刷中 Issue: 4 Pages: 398-404
  • DOI: 10.1007/s12185-015-1750-z
  • Peer Reviewed
• [Journal Article] CD30-positive primary bone marrow lymphoma mimicking Hodgkin lymphoma (2015)
  • Author(s): Suzuki T, Kusumoto S, Masaki A, Ishida T, Inagaki H, Iida S, Mori F.
  • Journal Title: International Journal of Hematology Volume: 印刷中 Issue: 2 Pages: 109-11
  • DOI: 10.1007/s12185-014-1714-8
  • Peer Reviewed
• [Journal Article] Prognostic impact of miR-145 down-regulation in adult T-cell leukemia/ lymphoma. (2014)
  • Author(s): 11.Xia H, Yamada S, Aoyama M, Sato F, Masaki A, Ge Y, Ri M, Ishida T, Ueda R, Utsunomiya A, Asai K, Inagaki H.
  • Journal Title: Hum Pathol. Volume: 45 Pages: 1192-1198
  • Peer Reviewed
• [Journal Article] Antitumor effects of bevacizumab in a microenvironment-dependent human adult T-cell leukemia/lymphoma mouse model. (2014)
  • Author(s): 10.Mori F, Ishida T, Ito A, Sato F, Masaki A, Narita T, Suzuki S, Yamada T, Takino H, Ri M, Kusumoto S, Komatsu H, Hishizawa M, Imada K, Takaori-Kondo A, Niimi A, Ueda R, Inagaki H, Iida S.
  • Journal Title: Eur J Haematol. Volume: 92 Pages: 219-228
  • Peer Reviewed / Acknowledgement Compliant
• [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. (2014)
  • Author(s): 9.Nakano N, Kusumoto S, Tanaka Y, Ishida T, Takeuchi S, Takatsuka Y, Akinaga S, Mizokami M, Ueda R, Utsunomiya A.
  • Journal Title: Hepatol Res. Volume: 44 Pages: 354-357
  • Peer Reviewed
• [Journal Article] HTLV-1 bZIP factor specific CD4 T cell responses in ATL patients after allogeneic hematopoietic stem cell transplantation. (2014)
  • Author(s): 8.Narita T, Ishida T, Masaki A, Suzuki S, Ito A, Mori F, Yamada T, Masaki Ri, Kusumoto S, Komatsu H, Miyazaki Y, Takatsuka Y, Utsunomiya A, Niimi A, Iida S, Ueda R
  • Journal Title: J Immunol. Volume: 192 Pages: 940-947
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-CCR4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. (2014)
  • Author(s): 7.Ogura M*, Ishida T*, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R.
  • Journal Title: J Clin Oncol. Volume: 32 Pages: 1157-1163
  • 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] 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] 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] Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rγnull mouse model. (2013)
  • Author(s): Masaki A, Ishida T, Suzuki S, Ito A, Mori F, Sato F, Narita T, Yamada T, Ri M, Kusumoto S, Komatsu H, Tanaka Y, Niimi A, Inagaki H, Iida S, Ueda R.
  • Journal Title: The journal of Immunology Volume: 191 (1) Issue: 1 Pages: 135-144
  • DOI: 10.4049/jimmunol.1202692
  • Peer Reviewed
• [Journal Article] Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma. (2013)
  • Author(s): Inagaki A, Tajima E, Uranishi M, Totani H, Asao Y, Ogura H, Masaki A, Yoshida T, Mori F, Ito A, Yano H, Ri M, Kayukawa S, Kataoka T, Kusumoto S, Ishida T, Hayami Y, Hanamura I, Komatsu H, Inagaki H, Matsuda Y, Ueda R, Iida S.
  • Journal Title: Leukemia Research Volume: 37 (12) Issue: 12 Pages: 1648-1655
  • DOI: 10.1016/j.leukres.2013.09.026
  • Peer Reviewed
• [Journal Article] Impact of graft-versus-host disease on allogeneic hematopoietic cell transplantation for adult T cell leukemia-lymphoma focusing on preconditioning regimens: nationwide retrospective study. (2013)
  • Author(s): Ishida T, Hishizawa M, Kato K, Tanosaki R, Fukuda T, Takatsuka Y, Eto T, Miyazaki Y, Hidaka M, Uike N, Miyamoto T, Tsudo M, Sakamaki H, Morishima Y, Suzuki R, Utsunomiya A.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 19(12) Issue: 12 Pages: 1731-1739
  • DOI: 10.1016/j.bbmt.2013.09.014
  • Peer Reviewed
• [Presentation] Multicenter Phase II Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (2015)
  • Author(s): Fujiwara H, Ishida T, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T,
  • Organizer: American Society of Hematology 57th Annual Meeting & Exposition
  • Place of Presentation: Orland, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Randomized phase II study of mogamulizumab (KW-0761) plus VCAP-AMP-VECP (mLSG15) versus mLSG15 alone for newly diagnosed aggressive adult T-cell leukemia-lymphoma (ATL). (2013)
  • Author(s): Jo T, Ishida T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Tomonaga M, Ueda R.
  • Organizer: 2013 ASCO Annual Meeting
  • Place of Presentation: McCormick Place, Chicago, USA
• [Presentation] The Efficacy and Safety of Mogamulizumab (KW-0761) in Multicenter Phase II Study for Patients with Relapsed Peripheral or Cutaneous T-Cell Lymphoma (2013)
  • Author(s): Ueda R, Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M.
  • Organizer: 12th International Conference on Malignant Lymphoma.
  • Place of Presentation: Palazzo dei Congressi, Lugano, Switzerland
• [Presentation] Combination of Mogamulizumab (KW-0761) with VCAP-AMP-VECP (mLSG15) is Well Tolerated and Effective as an Initial Therapy for Aggressive Adult T-Cell Leukaemia-Lymphoma (2013)
  • Author(s): Takemoto S, Ishida T, Jo T, Uozumi K, Suzushima H, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Tsukasaki K, Tomonaga M, Ueda R.
  • Organizer: 12th International Conference on Malignant Lymphoma.
  • Place of Presentation: Palazzo dei Congressi, Lugano, Switzerland