腫瘍免疫に基づくホジキンリンパ腫の病態解明と新規治療法の開発研究

• 研究課題/領域番号: 19390266
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 血液内科学
• 研究機関: 名古屋市立大学
• 研究代表者: 上田 龍三 名古屋市立大学, 大学院・医学研究科, 教授 (20142169)
• 研究分担者: 小松 弘和 名古屋市立大学, 大学院・医学研究科, 准教授 (60336675) ; 石田 高司 名古屋市立大学, 大学院・医学研究科, 講師 (80405183) ; 稲垣 宏 名古屋市立大学, 大学院・医学研究科, 教授 (30232507)
• 研究期間 (年度): 2007 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 17,680千円 (直接経費: 13,600千円、間接経費: 4,080千円); 2009年度: 4,420千円 (直接経費: 3,400千円、間接経費: 1,020千円); 2008年度: 4,420千円 (直接経費: 3,400千円、間接経費: 1,020千円); 2007年度: 8,840千円 (直接経費: 6,800千円、間接経費: 2,040千円)
• キーワード: ホジキンリンパ腫 / 腫瘍免疫 / CCR4 / EBウィルス / MUM1 / IRF-4 / EBウイルス

研究概要

腫瘍組織に浸潤するリンパ球(TIL : Tumor infiltrating lymphocyte)中のTregの存在は、様々ながんにおいて腫瘍細胞を宿主の免疫応答から回避させるだけでなく、癌ワクチンなどの癌免疫療法が未だ十分な効果をあげられない一因と考えられており、この制御性T細胞の制御は癌免疫療法が克服すべき大きな課題と考えられている。NOGマウスを用いたホジキンリンパ腫モデルにおいてCCR4抗体の投与はホジキンリンパ腫周囲のTregの数を減少せしめた。CCR4抗体はホジキンリンパ腫のみならず、様々ながんに対し、新しい概念の薬剤としての臨床応用が期待される。

研究成果

• [雑誌論文] Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma (ATLL). (2010)
  • 著者名/発表者名: Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, Iida S, Imada K, Uchiyama T, Akinaga S, Shitara K, Ueda R.
  • 雑誌名: Clin Cancer Res. 16 ページ: 1520-1531
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: J Clin Oncol. 28 ページ: 1591-8
  • 査読あり
• [雑誌論文] Phase I study of KW-0761, a defucosylated anit-CCR4 antibody, in relapsed patients with adult T-cell leukemia lymphoma and peripheral T-cell lymphoma (2010)
  • 著者名/発表者名: Yamamoto K
  • 雑誌名: J Clin Oncol. 28(9) ページ: 1591-8
  • 査読あり
• [雑誌論文] Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma (2010)
  • 著者名/発表者名: Ishii T
  • 雑誌名: Clin Cancer Res 16(5) ページ: 1520-1531
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: J Immunol. 183 ページ: 4782-91
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: Blood. 114 ページ: 3325-8
  • 査読あり
• [雑誌論文] Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC. (2009)
  • 著者名/発表者名: Inagaki A, Ishida T, Yano H, Ishii T, Kusumoto S, Ito A, Ri M, Mori F, Ding J, Komatsu H, Iida S, Ueda R.
  • 雑誌名: Int J Cancer. 125 ページ: 212-21
  • 査読あり
• [雑誌論文] Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1. (2009)
  • 著者名/発表者名: Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, Ding J, Kusumoto S, Komatsu H, Utsunomiya A, Ueda R.
  • 雑誌名: Cancer Sci. 100 ページ: 341-8
  • NAID: 10025142727
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: Cancer Immunol Immunother. 58 ページ: 1195-206
  • 査読あり
• [雑誌論文] Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL cells mediated by autologous human immune cells inNOD/Shi-scid,, IL-2R gamma(null)mice in vivo (2009)
  • 著者名/発表者名: Ito A
  • 雑誌名: J Immunol 183(7) ページ: 4782-91
  • 査読あり
• [雑誌論文] Anti-CCR4 monoclonal antibody as a novel therapy for advanced mycosis fungoides and Sezary syndrome (2009)
  • 著者名/発表者名: Yano H
  • 雑誌名: Rinsho Ketsueki 50(12) ページ: 1671-8
  • 査読あり
• [雑誌論文] The role of physicians in charge of cancer chemotherapy in oncological management (2009)
  • 著者名/発表者名: Kusumoto S
  • 雑誌名: Nippon Naika Gakkai Zasshi 98(8) ページ: 1947-51
  • 査読あり
• [雑誌論文] Small-cell lung cancer arising after chemotherapy for a patient with lymphoma of pulmonary mucosa-associated lymphoid tissue-a case report (2009)
  • 著者名/発表者名: NaKao M
  • 雑誌名: Gan To Kagaku Ryoho 36(10) ページ: 1711-4
  • 査読あり
• [雑誌論文] Significance of thymidylate synthase for resistance to pemetrexed in lung cancer (2009)
  • 著者名/発表者名: Ozasa H
  • 雑誌名: Cacner Sci 101(1) ページ: 161-6
  • 査読あり
• [雑誌論文] Design, synthesis, enzyme inhibition and tumor cell growth inhibition of 2-anilinobenzamide derivatives as SIRT1 inhibitors (2009)
  • 著者名/発表者名: Suzuki T
  • 雑誌名: Bloorg Med Chem 17(16) ページ: 5900-5
  • 査読あり
• [雑誌論文] Expression of the ULBP ligands for NKG2D by B-NHL cellsplays an important role in determining their susceptibility to rituximab-induced ADCC (2009)
  • 著者名/発表者名: Inagaki A
  • 雑誌名: Int J Cancer 125(1) ページ: 212-21
  • 査読あり
• [雑誌論文] The Asn505 mutation of c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mplprotein due to strong amino acid polarity (2009)
  • 著者名/発表者名: Ding J
  • 雑誌名: Blood 114(15) ページ: 3325-8
  • 査読あり
• [雑誌論文] Busulfex(i.v.BU)and CY regimen before SCT : Japanese-targeted phase II pharmacokinetics combined study (2009)
  • 著者名/発表者名: Kim SW
  • 雑誌名: Bone Marrow Transplant 43(8) ページ: 611-7
  • 査読あり
• [雑誌論文] ABCC10/MRP7 is associated with vinorelbine resistance in no n-small cell lung cancer (2009)
  • 著者名/発表者名: Bessho Y
  • 雑誌名: Oncol Rep 21(1) ページ: 263-8
  • 査読あり
• [雑誌論文] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma. (2008)
  • 著者名/発表者名: 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.
  • 雑誌名: Cancer Sci. 99 ページ: 2309-14
  • NAID: 10024013572
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Yano H, Ishida T, Imada K, Sakai T, Ishii T, Inagaki A, Iida S, Uchiyama T, Ueda R.
  • 雑誌名: Br J Haematol. 140 ページ: 586-9
  • 査読あり
• [雑誌論文] Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. (2008)
  • 著者名/発表者名: 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.
  • 雑誌名: Mol Cancer Ther. 7 ページ: 1461-71
  • 査読あり
• [雑誌論文] Combinations of tumor-specific CD8+ CTLs and anti-CD25 mAb provide improved immunotherapy. (2008)
  • 著者名/発表者名: Ohmura Y, Yoshikawa K, Saga S, Ueda R, Kazaoka Y, Yamada S.
  • 雑誌名: Oncol Rep. 19 ページ: 1265-70
  • 査読あり
• [雑誌論文] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerse I inhibitor, irinotecan (CPT- 11), for multiple myeloma (2008)
  • 著者名/発表者名: Yano H
  • 雑誌名: Cancer Sci. 99(11) ページ: 2309-14
  • 査読あり
• [雑誌論文] Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model (2008)
  • 著者名/発表者名: Ito A
  • 雑誌名: Cancer Immunol Immunother (印刷中in press)
  • 査読あり
• [雑誌論文] Bortwzomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1. (2008)
  • 著者名/発表者名: Ri M
  • 雑誌名: Cancer Sci. (印刷中in press)
  • 査読あり
• [雑誌論文] Defucosylated anti-CCR4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/ refractory mycosis fungoides and sezary syndrome. (2007)
  • 著者名/発表者名: Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R.
  • 雑誌名: Clin Cancer Res. 13 ページ: 6494-500
  • 査読あり
• [雑誌論文] Regulatory T-cell Function of adult T-cell leukemia/lymphoma cells. (2007)
  • 著者名/発表者名: Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R.
  • 雑誌名: Int J Cancer. 120 ページ: 2052-7
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: J Clin Oncol. 25 ページ: 5458-64
  • 査読あり
• [雑誌論文] Prognostic Significance of NPM-ALK Fusion Transcript Overexpression in ALK-positive Anaplastic Large Cell Lymphoma. (2007)
  • 著者名/発表者名: Li C, Takino H, Eimoto T, Ishida T, Inagaki A, Ueda R, Suzuki R, Yoshino T, Nakagawa A, Nakamura S, Inagaki H.
  • 雑誌名: Mod Pathol. 20 ページ: 648-55
  • 査読あり
• [雑誌論文] Clinical Significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor. (2007)
  • 著者名/発表者名: Utsunomiya A, Ishida T, Inagaki A, Ishii T, Yano H, Komatsu H, Iida S, Yonekura K, Takeuchi S, Takatsuka Y, Ueda R.
  • 雑誌名: Leuk Res. 31 ページ: 915-20
  • 査読あり
• [雑誌論文] Differing distributions of CXCR3-andCCR4-positive cells among types of interstit l pneumonia associated with collagen vascular diseases. (2007)
  • 著者名/発表者名: Shimizu S, Yoshinouchi T, Niimi T, Ohtsuki Y, Fuzita J, Maeda H, Sato S, Yamadori I, Eimoto T, Ueda R.
  • 雑誌名: Virchows Arch. 450 ページ: 51-8
  • 査読あり
• [雑誌論文] Expression of chemokine receptors CXCR3 and CCR4 in lymphocytes of idiopathic nonspecific interstitial pneumonia. (2007)
  • 著者名/発表者名: Yoshinouchi T, Naniwa T, Shimizu S, Ohtsuki Y, Fujita J, Sato S, Eimoto T, Ueda R.
  • 雑誌名: Respir Med. 101 ページ: 1258-64
  • 査読あり
• [雑誌論文] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. (2007)
  • 著者名/発表者名: Sanda, T.
  • 雑誌名: Haematologica 92(1) ページ: 115-20
  • 査読あり
• [雑誌論文] Regulatory T-cell function of adult T-cell leukemia/lymphoma cells. (2007)
  • 著者名/発表者名: Yano, H.
  • 雑誌名: Int J Cancer 120(9) ページ: 2052-2057
  • 査読あり
• [雑誌論文] Long-term Follow-up of 14 Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia following Autologous Bone Marrow Transplantation in First Complete Remission (2007)
  • 著者名/発表者名: Mizuta, S.
  • 雑誌名: Int J Hematol. 85(2) ページ: 140-5
  • 査読あり
• [雑誌論文] Immunoglobuiln VH gene analysis in gastric MALT lymphomas. (2007)
  • 著者名/発表者名: Sakuma, H.
  • 雑誌名: Mod Pathol. 20(4) ページ: 460-466
  • 査読あり
• [雑誌論文] Prognostic significance of NPM-ALKfusion transcript overexpression in ALK-positive anaplastic large-cell Iymphoma (2007)
  • 著者名/発表者名: Li, C.
  • 雑誌名: Modern Pathology 20 ページ: 648-655
  • 査読あり
• [雑誌論文] Clinical significance of a blood eosinophilia in adult T-cell leuzkemia /lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor. (2007)
  • 著者名/発表者名: Utsunomiya, A.
  • 雑誌名: Leuk Res. 31(7) ページ: 915-20
  • 査読あり
• [雑誌論文] Differing distributions of CXCR3-and CCR4 -positive cells among types of interstitial pneumonia associated with collagen vascular diseases. (2007)
  • 著者名/発表者名: Shimizu, S.
  • 雑誌名: Virchows Arch. 450(1) ページ: 51-58
  • 査読あり
• [雑誌論文] VCAP-AMP-VECP Compared With Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801. (2007)
  • 著者名/発表者名: Tsukasaki, K.
  • 雑誌名: J Clin Oncol. 25(34) ページ: 5458-64
  • 査読あり
• [雑誌論文] Defucosylated Anti CC Chemokine Receptor 4 Monoclonal Antibody Combined with Immunomodulatory Cytokines: A Novel Immunotherapy for Aggressive/Refractory Mycosis Fungoides and Sezary Syndrome. (2007)
  • 著者名/発表者名: Yano, H.
  • 雑誌名: Clin Cancer Res. 13(21) ページ: 6494-6500
  • 査読あり
• [雑誌論文] POU2AF1, an amplification target at 11q23, priomotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17. (2007)
  • 著者名/発表者名: Zhao, C.
  • 雑誌名: Oncogene 27(1) ページ: 63-75
  • 査読あり
• [学会発表] CCR4 as a novel specific molecular target for immunotherapy in ATLL. (2010)
  • 著者名/発表者名: Ueda R.
  • 学会等名: 8th AACR/JCB Conference. 5-9 February
  • 発表場所: Waikoloa, Hawaii
• [学会発表] The CCR4 as a novel specific molecular target for immunotherapy in ATL (2008)
  • 著者名/発表者名: Ishida, T.
  • 学会等名: 第67回日本癌学会学術総会
  • 発表場所: 名古屋国際会議場
  • 年月日: 2008-10-29
• [学会発表] 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)
  • 著者名/発表者名: Yamamoto K, Tobinai K, Utsunomiya A, Tsukasaki K, Uike N, Uozumi K, Tomonaga M, Matsushima K, Shitara K, Akinaga S, Ueda R.
  • 学会等名: The 50th Annual Meeting of American Society of Hematology
  • 発表場所: San Francisco, CA, USA