Susumu Suzuki

Publications (6)24.66 Total impact

• Article: Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell-Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model.

  Ayako Masaki, Takashi Ishida, Susumu Suzuki, Asahi Ito, Fumiko Mori, Fumihiko Sato, Tomoko Narita, Tomiko Yamada, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Yuetsu Tanaka, Akio Niimi, Hiroshi Inagaki, Shinsuke Iida, Ryuzo Ueda
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  ABSTRACT: We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer.
  The Journal of Immunology 06/2013; · 5.79 Impact Factor
• Article: Angioimmunoblastic T-cell lymphoma mice model.

  Fumihiko Sato, Takashi Ishida, Asahi Ito, Fumiko Mori, Ayako Masaki, Hisashi Takino, Tomoko Narita, Masaki Ri, Shigeru Kusumoto, Susumu Suzuki, Hirokazu Komatsu, Akio Niimi, Ryuzo Ueda, Hiroshi Inagaki, Shinsuke Iida
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  ABSTRACT: We established an angioimmunoblastic T-cell lymphoma (AITL) mouse model using NOD/Shi-scid, IL-2Rγ(null) mice as recipients. The immunohistological findings of the AITL mice were almost identical to those of patients with AITL. In addition, substantial amounts of human immunoglobulin G/A/M were detected in the sera of the AITL mice. This result indicates that AITL tumor cells helped antibody production by B cells or plasma cells. This is the first report of reconstituting follicular helper T (TFH) function in AITL cells in an experimental model, and this is consistent with the theory that TFH cell is the cell of origin of AITL tumor cells.
  Leukemia research 09/2012; · 2.36 Impact Factor
• Article: Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma.

  Susumu Suzuki, Ayako Masaki, Takashi Ishida, Asahi Ito, Fumiko Mori, Fumihiko Sato, Tomoko Narita, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Yasuo Fukumori, Hiroyoshi Nishikawa, Yuetsu Tanaka, Akio Niimi, Hiroshi Inagaki, Shinsuke Iida, Ryuzo Ueda
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  ABSTRACT: We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL.
  Cancer Science 06/2012; 103(10):1764-73. · 3.33 Impact Factor
• Article: Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model

  Asahi Ito, Takashi Ishida, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Fumihiko Sato, Hisashi Takino, Fumiko Mori, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda
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  ABSTRACT: PurposeThere are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials. Experimental designNOD/Shi-scid, IL-2Rγnull (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors. ResultsHumanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice. ConclusionsAnti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy.
  Cancer Immunology and Immunotherapy 04/2012; 58(8):1195-1206. · 3.70 Impact Factor
• Article: Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2R gamma(null) mice in vivo.

  Asahi Ito, Takashi Ishida, Atae Utsunomiya, Fumihiko Sato, Fumiko Mori, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Hisashi Takino, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda
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  ABSTRACT: There is a lack of suitable small animal models to evaluate human Ab-dependent cellular cytotoxicity (ADCC) in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. In the present study, we used NOG mice bearing primary adult T cell leukemia/lymphoma (ATLL) cells and a therapeutic chimeric anti-CCR4 mAb, the Fc region of which is defucosylated to enhance ADCC. We report significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. Human autologous ADCC in mice in vivo was confirmed by the depletion of human immune cells before ATLL PBMC inoculation. In addition, NOG mice bearing primary ATLL cells presented features identical with patients with ATLL. In conclusion, this approach makes it possible to model the human immune system active in Ab-based immunotherapy in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb. Furthermore, the potent ADCC mediated by defucosylated anti-CCR4 mAb, observed here in vivo in humanized mice, will be exploited in clinical trials in the near future.
  The Journal of Immunology 10/2009; 183(7):4782-91. · 5.79 Impact Factor
• 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.

  Asahi Ito, Takashi Ishida, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Fumihiko Sato, Hisashi Takino, Fumiko Mori, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda
  [show abstract] [hide abstract]
  ABSTRACT: There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials. NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors. Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice. Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy.
  Cancer Immunology and Immunotherapy 01/2009; 58(8):1195-206. · 3.70 Impact Factor