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  1. Article: Progress in Natural Killer T Cell-Based Immunotherapy for Cancer: Use of Allogeneic and Gene-Edited Cells.

    Aoki, Takahiro / Motohashi, Shinichiro

    Critical reviews in oncogenesis

    2024  Volume 29, Issue 1, Page(s) 1–9

    Abstract: Immune cell therapy has received attention in the clinical setting. However, current chimeric antigen receptor T cell therapies require individualized manufacturing based on patient cells, resulting in high costs and long processing times. Allogeneic ... ...

    Abstract Immune cell therapy has received attention in the clinical setting. However, current chimeric antigen receptor T cell therapies require individualized manufacturing based on patient cells, resulting in high costs and long processing times. Allogeneic immune cell therapy, which involves the use of immune cells from other donors, is emerging as a promising alternative that offers multiple advantages, including off-the-shelf availability, standardized manufacturing, and potentially stronger effector functions. Natural killer T (NKT) cells are a type of T cell that can be activated without being restricted by HLA, indicating their potential use in allogeneic cell immunotherapy. They exhibit cytotoxic activity against various cancer targets. However, their low frequency in blood limits their use in ex vivo amplification for treatment. This has led researchers to focus on allogeneic NKT cells as a potential treatment agent. In this study, we review the research on NKT cell-based immunotherapy and focus on the recent progress in clinical trials related to NKT cell-based immunotherapy worldwide. NKT cell-based therapy is not limited to specific cancer types and has been investigated in many ways worldwide over the past decade. Some clinical trials targeting NKT cells have shown promising results; however, the number of trials is low compared to those using T and natural killer cells. The use of allogeneic NKT cells may revolutionize the treatment of cancer and other diseases. However, further research and clinical trials are necessary to fully understand their efficacy, safety, and long-term benefits.
    MeSH term(s) Humans ; Natural Killer T-Cells ; Gene Editing ; Immunotherapy ; Neoplasms/genetics ; Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation
    Language English
    Publishing date 2024-02-29
    Publishing country United States
    Document type Review ; Journal Article
    ZDB-ID 1036388-9
    ISSN 0893-9675
    ISSN 0893-9675
    DOI 10.1615/CritRevOncog.2023049526
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: [Cancer Immunotherapy Using Allogeneic NKT Cells].

    Aoki, Takahiro / Motohashi, Shinichiro

    Gan to kagaku ryoho. Cancer & chemotherapy

    2023  Volume 50, Issue 5, Page(s) 584–588

    Abstract: We have developed autologous NKT cell-targeted immunotherapy for lung cancer and head and neck cancer at Chiba University. We induce α-galactosylceramide(αGalCer)-pulsed antigen-presenting cells(APCs)from patients' peripheral blood mononuclear cells( ... ...

    Abstract We have developed autologous NKT cell-targeted immunotherapy for lung cancer and head and neck cancer at Chiba University. We induce α-galactosylceramide(αGalCer)-pulsed antigen-presenting cells(APCs)from patients' peripheral blood mononuclear cells(PBMCs)in vitro and give them back to the patients. We transferred them intravenously to patients with lung cancer and demonstrated the potential to improve survival time. For patients with head and neck cancer, we transferred them via the nasal submucosa with ex vivo expanded autologous NKT cells. We demonstrated an increased response rate compared with αGalCer-pulsed APCs alone. This suggested that combination therapy of αGalCer-pulsed APCs and NKT cells can increase the response rate. However, NKT cells circulate at less than 0.1% in human PBMCs. Producing enough autologous NKT cells for adoptive immunotherapy is tough. Furthermore, the immunologic function of patient-derived NKT cells can vary among patients. Because stable cell production in number and nature is essential to show effective treatment results, the development of NKT cell-targeted immunotherapy is moving forward using allogeneic NKT cells worldwide. In this circumstance, we, RIKEN and Chiba University, have been developing allogeneic induced pluripotent stem cell(iPS cell)- derived NKT cell therapy. The phase Ⅰ clinical trial of iPS cell-derived NKT cell therapy for head and neck cancer is ongoing.
    MeSH term(s) Humans ; Head and Neck Neoplasms ; Hematopoietic Stem Cell Transplantation ; Immunotherapy ; Lung Neoplasms/therapy ; Natural Killer T-Cells
    Language Japanese
    Publishing date 2023-05-22
    Publishing country Japan
    Document type Clinical Trial ; English Abstract ; Journal Article
    ZDB-ID 604842-0
    ISSN 0385-0684
    ISSN 0385-0684
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy.

    Aoki, Takahiro / Motohashi, Shinichiro / Koseki, Haruhiko

    Inflammation and regeneration

    2023  Volume 43, Issue 1, Page(s) 27

    Abstract: Invariant natural killer T (iNKT) cells are a subset of innate-like T cells restricted by a major histocompatibility complex (MHC) class I-like molecule, CD1d. iNKT cells express an invariant T cell receptor (TCR) encoded by Vα14 Jα18 in mice and Vα24 ... ...

    Abstract Invariant natural killer T (iNKT) cells are a subset of innate-like T cells restricted by a major histocompatibility complex (MHC) class I-like molecule, CD1d. iNKT cells express an invariant T cell receptor (TCR) encoded by Vα14 Jα18 in mice and Vα24 Jα18 in humans and are activated by recognizing glycolipid antigens, such as α-galactosylceramide (αGalCer), presented by CD1d. iNKT cells exhibit anti-tumor activity via their NK-like cytotoxicity and adjuvant activity. Although iNKT cell-targeted immunotherapy is a conceptually promising approach, we still found a technical hurdle for its clinical implementation which is mainly due to the low frequency of iNKT cells, particularly in humans. To compensate for this, we proposed to generate adequate numbers of clinically competent NKT cells from induced pluripotent stem cells (iPSCs) for cancer immunotherapy. Toward this goal, we first obtained the proof of concept (POC) for this approach in mice. We developed a technology to differentiate iPSCs into iNKT cells (iPSC-iNKT cells) and found iPSC-iNKT cells efficiently rejected a syngeneic experimental thymoma by inducing antigen-specific CD8 T cells. After achieving the POC in mice, we developed human iPSC-iNKT cells, which had a high correlation in their gene expression profiles with parental iNKT cells. Human iPSC-iNKT cells also exhibited anti-tumor activity and adjuvant activity for human NK cells in vivo. Based on this supporting evidence for the anti-tumor activity of human iPSC-iNKT cells, we began to generate good manufacturing practice (GMP)-grade iPSC-iNKT cells. As of now, the first-in-human clinical trial of iPSC-iNKT cell therapy is ongoing as a single-agent, dose-escalation study for patients with advanced head and neck cancer. Demonstration of the safety of iPSC-iNKT cell therapy may allow us to improve the strategy by further reinforcing the therapeutic activity of iPSC-iNKT, cells either by gene-editing or combinatorial use with other immune cell products such as dendritic cells. Sixteen years after the establishment of the iPSC technology, we are reaching the first checkpoint to evaluate the clinical efficacy of iPSC-derived immune cells.
    Language English
    Publishing date 2023-05-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2051471-2
    ISSN 1880-9693 ; 0389-4290
    ISSN 1880-9693 ; 0389-4290
    DOI 10.1186/s41232-023-00275-5
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  4. Article ; Online: Anti-Vα24Jα18 TCR Antibody Tunes iNKT Cell Responses to Target and Kill CD1d-negative Tumors in an FcγRII (CD32)-dependent Manner.

    Takami, Mariko / Aoki, Takahiro / Nishimura, Katsuhiro / Tanaka, Hidekazu / Onodera, Atsushi / Motohashi, Shinichiro

    Cancer research communications

    2024  Volume 4, Issue 2, Page(s) 446–459

    Abstract: Invariant natural killer T (iNKT) cells play an essential role in antitumor immunity by exerting cytotoxicity and producing massive amounts of cytokines. iNKT cells express invariant T-cell receptors (TCR) to recognize their cognate glycolipid antigens ... ...

    Abstract Invariant natural killer T (iNKT) cells play an essential role in antitumor immunity by exerting cytotoxicity and producing massive amounts of cytokines. iNKT cells express invariant T-cell receptors (TCR) to recognize their cognate glycolipid antigens such as α-galactosylceramide (α-GalCer) presented on CD1d. We recently reported that iNKT cells recognize CD1d-negative leukemia cell line K562 in a TCR-dependent manner. However, it remains controversial how iNKT cells use TCRs to recognize and exhibit cytotoxic activity toward CD1d-negative tumors cells without CD1d restriction. Here, we report that iNKT cells exerted cytotoxicity toward K562 cells via a carried over anti-Vα24 TCR mAb from positive selection by magnetic bead sorting. We found that addition of the anti-Vα24Jα18 TCR mAb (6B11 mAb) rendered iNKT cells cytotoxic to K562 cells in an FcγRII (CD32)-dependent manner. Moreover, iNKT cells treated with 6B11 mAb became cytotoxic to other CD32+ cell lines (U937 and Daudi). In addition, iNKT cells treated with 6B11 mAb suppressed K562 cell growth in a murine xenograft model in vivo. These data suggest that anti-iNKT TCR mAb treatment of iNKT cells can be applied as a therapeutic strategy to treat CD32+ cancers such as leukemia, lymphoma, and lung cancer.
    Significance: Our findings unveiled that iNKT cells recognize and kill CD1d-negative target tumors via the anti-iNKT TCR mAb bound to CD32 at the tumor site, thereby bridging iNKT cells and CD1d-negative tumors. These findings shed light on the therapeutic potential of anti-iNKT TCR mAbs in NKT cell-based immunotherapy to treat CD1d-negative CD32+ cancers.
    MeSH term(s) Humans ; Mice ; Animals ; Natural Killer T-Cells ; Receptors, Antigen, T-Cell/metabolism ; Cell Line ; Cytokines/metabolism ; Leukemia/metabolism
    Chemical Substances Receptors, Antigen, T-Cell ; Cytokines
    Language English
    Publishing date 2024-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.CRC-23-0203
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: [III. Immunotherapy for lung cancer].

    Motohashi, Shinichiro

    Gan to kagaku ryoho. Cancer & chemotherapy

    2013  Volume 40, Issue 8, Page(s) 1015–1017

    MeSH term(s) Humans ; Immunotherapy ; Lung Neoplasms/immunology ; Lung Neoplasms/therapy ; Natural Killer T-Cells/immunology
    Language Japanese
    Publishing date 2013-08
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 604842-0
    ISSN 0385-0684
    ISSN 0385-0684
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  6. Article: Targeting PD-1/PD-L1 inhibits rejection in a heterotopic tracheal allograft model of lung transplantation.

    Kaiho, Taisuke / Suzuki, Hidemi / Hata, Atsushi / Matsumoto, Hiroki / Tanaka, Kazuhisa / Sakairi, Yuichi / Motohashi, Shinichiro / Yoshino, Ichiro

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1298085

    Abstract: Immune checkpoint molecules such as programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have revolutionized the field of lung cancer treatment. As part of our study, we examined the role of these proteins in acute rejection in a mouse model ... ...

    Abstract Immune checkpoint molecules such as programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have revolutionized the field of lung cancer treatment. As part of our study, we examined the role of these proteins in acute rejection in a mouse model of heterotopic tracheal transplantation. Recipient mice were untreated (Allo group) or treated with anti-PD-L1 (aPDL1 group) or PD-L1 Fc recombinant protein (PD-L1 Fc group). A further group of C57BL/6 mice received isografts (Iso group). The occlusion rate was significantly higher in the Allo group than in the Iso group (
    Language English
    Publishing date 2023-11-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1298085
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  7. Article: Invariant NKT cell-based immunotherapy for lung cancer and head and neck cancer.

    Ihara, Fumie / Motohashi, Shinichiro

    Nihon rinsho. Japanese journal of clinical medicine

    2018  Volume 75, Issue 2, Page(s) 312–316

    Abstract: CD1d-restricted invariant natural killer T (iNKI) cells are the unique lymphocyte subpopu- lation that interacts with glycolipid via the invariant T cell receptor. Ligand activated iNKT cells produce a variety of cytokines, and thus bridging the innate ... ...

    Abstract CD1d-restricted invariant natural killer T (iNKI) cells are the unique lymphocyte subpopu- lation that interacts with glycolipid via the invariant T cell receptor. Ligand activated iNKT cells produce a variety of cytokines, and thus bridging the innate and adaptive immune sys- tems. Since recent studies have highlighted iNKT cells to have potent anti-tumor effects, greater attention are being given to the development of iNKT cell-based immunotherapy for advanced solid tumors. This article summarizes the progress of our recent works on active immunotherapies aiming at the augmentation of iNKT cell function in vivo in patients with non-small cell lung cancer, and discusses the role of iNKT cell-induced immune responses in cancer immunotherapy.
    MeSH term(s) Head and Neck Neoplasms/immunology ; Head and Neck Neoplasms/therapy ; Humans ; Immunotherapy ; Lung Neoplasms/immunology ; Lung Neoplasms/therapy ; Natural Killer T-Cells/immunology
    Language Japanese
    Publishing date 2018-12-16
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 390903-7
    ISSN 0047-1852
    ISSN 0047-1852
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: [Application of iPS Cell-Derived NKT Cells to Cancer Immunotherapy].

    Motohashi, Shinichiro / Iinuma, Tomohisa / Kurokawa, Tomoya / Koseki, Haruhiko

    Gan to kagaku ryoho. Cancer & chemotherapy

    2020  Volume 47, Issue 10, Page(s) 1411–1414

    Abstract: NKT cells are innate lymphocytes that express an invariant T cell receptor. Since activated NKT cells exert strong anti-tumor responses, NKT cells have been intensively studied for the purpose of their application to cancer immunotherapeutic approaches. ... ...

    Abstract NKT cells are innate lymphocytes that express an invariant T cell receptor. Since activated NKT cells exert strong anti-tumor responses, NKT cells have been intensively studied for the purpose of their application to cancer immunotherapeutic approaches. Although human peripheral blood contained a very low fraction of NKT cells, and decreased number of NKT cells was also demonstrated in cancer-bearing patients, peripheral blood NKT cells can be activated by ligand-pulsed antigen presenting cells, and can produce a large amount of interferon-γ upon activation. The clinical trials of adoptive transfer of autologous NKT cells were already performed in patients with non-small cell lung cancer, and with head and neck cancer at Chiba University to show its effectiveness and limitation. Meanwhile, RIKEN reported NKT cell regeneration using iPS cell technology in mice, and subsequently established a protocol for regenerating NKT cells from human peripheral blood NKT cells using iPS cell technology. It was confirmed that the iPS cell-derived NKT cells (iPS-NKT) have sufficient expansion c apacity and potent direct and indirect cytotoxic activity in the humanized mice models, which suggests their therapeutic competence. We are currently planning an investigator-initiated clinical trial of allogeneic iPS-NKT cell therapy for head and neck cancer.
    MeSH term(s) Animals ; Carcinoma, Non-Small-Cell Lung ; Humans ; Immunotherapy ; Induced Pluripotent Stem Cells ; Lung Neoplasms ; Mice ; Natural Killer T-Cells
    Language Japanese
    Publishing date 2020-10-31
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 604842-0
    ISSN 0385-0684
    ISSN 0385-0684
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  9. Article: [II. Overview and Future Outlook of Immune Cell Therapy for Lung Cancer].

    Ihara, Fumie / Motohashi, Shinichiro

    Gan to kagaku ryoho. Cancer & chemotherapy

    2017  Volume 44, Issue 8, Page(s) 650–654

    MeSH term(s) Animals ; B7-H1 Antigen/immunology ; Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy ; Lung Neoplasms/immunology ; Lung Neoplasms/therapy ; Natural Killer T-Cells/immunology ; Recurrence
    Chemical Substances B7-H1 Antigen ; CD274 protein, human
    Language Japanese
    Publishing date 2017-08
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 604842-0
    ISSN 0385-0684
    ISSN 0385-0684
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  10. Article: Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation.

    Matsumoto, Hiroki / Suzuki, Hidemi / Yamanaka, Takahiro / Kaiho, Taisuke / Hata, Atsushi / Inage, Terunaga / Ito, Takamasa / Kamata, Toshiko / Tanaka, Kazuhisa / Sakairi, Yuichi / Motohashi, Shinichiro / Yoshino, Ichiro

    Life (Basel, Switzerland)

    2023  Volume 13, Issue 10

    Abstract: Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in ... ...

    Abstract Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.
    Language English
    Publishing date 2023-10-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662250-6
    ISSN 2075-1729
    ISSN 2075-1729
    DOI 10.3390/life13102042
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