Development of novel treatment strategy against Hodgkin lymphoma based on the immunopathogenesis

2009 Fiscal Year Final Research Report

• Project/Area Number: 19390266
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: UEDA Ryuzo Nagoya City University, 大学院・医学研究科, 教授 (20142169)
• Co-Investigator(Kenkyū-buntansha): KOMATSU Hirokazu 名古屋市立大学, 大学院・医学研究科, 准教授 (60336675) ; ISHIDA Takashi 名古屋市立大学, 大学院・医学研究科, 講師 (80405183) ; INAGAKI Hiroshi 名古屋市立大学, 大学院・医学研究科, 教授 (30232507)
• Project Period (FY): 2007 – 2009
• Keywords: ホジキンリンパ腫 / 腫瘍免疫 / CCR4 / EBウィルス / MUM1 / IRF-4

Research Abstract

We have demonstrated that the anti-CCR4 mAb reduces the number of Treg cells among TIL in an in vivo NOG mouse model (bearing human tumor & engrafted with human immune cells). These results indicate that use of anti-CCR4 mAb could represent a novel strategy for the treatment not only of Hodgkin lymphoma, but also many other types of cancer by overcoming suppressive effects of Treg cells on the host's immune response to tumor cells. In the near future, the efficacy of the anti-CCR4 mAb in the latter context will also be established in clinical trials in humans.

Research Products

• [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. 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. 28 Pages: 1591-8
  • Peer Reviewed
• [Journal Article] Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL Cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2Rgamma(null) mice in vivo. (2009)
  • Author(s): Ito A, Ishida T, Utsunomiya A, Sato F, Mori F, Yano H, Inagaki A, Suzuki S, Takino H, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R.
  • Journal Title: J Immunol. 183 Pages: 4782-91
  • Peer Reviewed
• [Journal Article] The Asn505 mutation of c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. (2009)
  • Author(s): Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A, Wakita A, Ishida T, Nitta M, Ueda R.
  • Journal Title: Blood. 114 Pages: 3325-8
  • Peer Reviewed
• [Journal Article] Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC. (2009)
  • Author(s): Inagaki A, Ishida T, Yano H, Ishii T, Kusumoto S, Ito A, Ri M, Mori F, Ding J, Komatsu H, Iida S, Ueda R.
  • Journal Title: Int J Cancer. 125 Pages: 212-21
  • Peer Reviewed
• [Journal Article] Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1. (2009)
  • Author(s): Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, Ding J, Kusumoto S, Komatsu H, Utsunomiya A, Ueda R.
  • Journal Title: Cancer Sci. 100 Pages: 341-8
  • Peer Reviewed
• [Journal Article] Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. (2009)
  • Author(s): 7. Ito A, Ishida T, Yano H, Inagaki A, Suzuki S, Sato F, Takino H, Mori F, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R.
  • Journal Title: Cancer Immunol Immunother. 58 Pages: 1195-206
  • Peer Reviewed
• [Journal Article] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma. (2008)
  • Author(s): Yano H, Kayukawa S, Iida S, Nakagawa C, Oguri T, Sanda T, Ding J, Mori F, Ito A, Ri M, Inagaki A, Kusumoto S, Ishida T, Komatsu H, Inagaki H, Suzuki A, Ueda R.
  • Journal Title: Cancer Sci. 99 Pages: 2309-14
  • Peer Reviewed
• [Journal Article] Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF. (2008)
  • Author(s): Yano H, Ishida T, Imada K, Sakai T, Ishii T, Inagaki A, Iida S, Uchiyama T, Ueda R.
  • Journal Title: Br J Haematol. 140 Pages: 586-9
  • Peer Reviewed
• [Journal Article] Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. (2008)
  • Author(s): Kondo E, Tanaka T, Miyake T, Ichikawa T, Hirai M, Adachi M, Yoshikawa K, Ichimura K, Ohara N, Moriwaki A, Date I, Ueda R, Yoshino T.
  • Journal Title: Mol Cancer Ther. 7 Pages: 1461-71
  • Peer Reviewed
• [Journal Article] Combinations of tumor-specific CD8+ CTLs and anti-CD25 mAb provide improved immunotherapy. (2008)
  • Author(s): Ohmura Y, Yoshikawa K, Saga S, Ueda R, Kazaoka Y, Yamada S.
  • Journal Title: Oncol Rep. 19 Pages: 1265-70
  • Peer Reviewed
• [Journal Article] Defucosylated anti-CCR4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/ refractory mycosis fungoides and sezary syndrome. (2007)
  • Author(s): Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R.
  • Journal Title: Clin Cancer Res. 13 Pages: 6494-500
  • Peer Reviewed
• [Journal Article] Regulatory T-cell Function of adult T-cell leukemia/lymphoma cells. (2007)
  • Author(s): Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R.
  • Journal Title: Int J Cancer. 120 Pages: 2052-7
  • Peer Reviewed
• [Journal Article] Japan Clinical Oncology Group Study JCOG9801. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. (2007)
  • Author(s): Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M.
  • Journal Title: J Clin Oncol. 25 Pages: 5458-64
  • Peer Reviewed
• [Journal Article] Prognostic Significance of NPM-ALK Fusion Transcript Overexpression in ALK-positive Anaplastic Large Cell Lymphoma. (2007)
  • Author(s): Li C, Takino H, Eimoto T, Ishida T, Inagaki A, Ueda R, Suzuki R, Yoshino T, Nakagawa A, Nakamura S, Inagaki H.
  • Journal Title: Mod Pathol. 20 Pages: 648-55
  • Peer Reviewed
• [Journal Article] Clinical Significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor. (2007)
  • Author(s): Utsunomiya A, Ishida T, Inagaki A, Ishii T, Yano H, Komatsu H, Iida S, Yonekura K, Takeuchi S, Takatsuka Y, Ueda R.
  • Journal Title: Leuk Res. 31 Pages: 915-20
  • Peer Reviewed
• [Journal Article] Differing distributions of CXCR3-andCCR4-positive cells among types of interstit l pneumonia associated with collagen vascular diseases. (2007)
  • Author(s): Shimizu S, Yoshinouchi T, Niimi T, Ohtsuki Y, Fuzita J, Maeda H, Sato S, Yamadori I, Eimoto T, Ueda R.
  • Journal Title: Virchows Arch. 450 Pages: 51-8
  • Peer Reviewed
• [Journal Article] Expression of chemokine receptors CXCR3 and CCR4 in lymphocytes of idiopathic nonspecific interstitial pneumonia. (2007)
  • Author(s): Yoshinouchi T, Naniwa T, Shimizu S, Ohtsuki Y, Fujita J, Sato S, Eimoto T, Ueda R.
  • Journal Title: Respir Med. 101 Pages: 1258-64
  • Peer Reviewed
• [Presentation] CCR4 as a novel specific molecular target for immunotherapy in ATLL. (2010)
  • Author(s): Ueda R.
  • Organizer: 8th AACR/JCB Conference. 5-9 February
  • Place of Presentation: Waikoloa, Hawaii
  • Year and Date: 20100000
• [Presentation] Phase I study of KW-0761, a Defucosylated Patients(Pts) with Adult T-Cell Leukemia-Lymphoma(ATLL) or Peripheral T-Cell Lymphoma(PTCL): Updated Results. (2008)
  • Author(s): Yamamoto K, Tobinai K, Utsunomiya A, Tsukasaki K, Uike N, Uozumi K, Tomonaga M, Matsushima K, Shitara K, Akinaga S, Ueda R.
  • Organizer: The 50th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 20081206-20081209