Kagoya, Yuki

写真a

Affiliation

School of Medicine, Institute for Advanced Medical Research Division of Tumor Immunology （Shinanomachi）

Position

Professor

E-mail Address

E-mail address

Related Websites

Contact Address

Shinanomachi 35, Shinjuku, Tokyo, Japan

Telephone No.

+81-3-5843-6174

Fax No.

+81-3-5843-6177
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Profile 【 Display / hide 】

  • Yuki Kagoya received his MD at the University of Tokyo in 2007 and completed clinical training for Internal Medicine, Hematology & Medical Oncology, and Transplantation Medicine. Dr. Kagoya was then involved in basic research on leukemia initiating cells during his PhD training. After obtaining PhD, he joined Dr. Naoto Hirano’s laboratory at Princess Margaret Cancer Centre, Toronto to be dedicated to research on cancer immunology and immunotherapy (2014-2018). He served on Aichi Cancer Center Research Institute as the Principal Investigator for 3 years prior to his recruitment to Keio University.

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Career 【 Display / hide 】

  • 2007.04
    -
    2009.03

    Kanto Rosai Hospital, 内科

  • 2013.04
    -
    2013.09

    The University of Tokyo, Faculty of Medicine University Hospital Heamatology and Oncology, Research Fellow

  • 2013.10
    -
    2014.05

    The University of Tokyo, Faculty of Medicine University Hospital Heamatology and Oncology, Assistant Professor

  • 2014.06
    -
    2018.05

    Princess Margaret Cancer Centre, Tumor Immunotherapy Program, Research Fellow

  • 2018.06
    -
    2019.09

    The University of Tokyo, Faculty of Medicine University Hospital, Assistant Professor

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Academic Background 【 Display / hide 】

  • 2001.04
    -
    2007.03

    The University of Tokyo, Faculty of Medicine, 医学科

  • 2009.04
    -
    2013.03

    The University of Tokyo, Graduate School of Medicine

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Academic Degrees 【 Display / hide 】

  • Ph.D., The University of Tokyo, Coursework, 2013.03

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Research Areas 【 Display / hide 】

  • Life Science / Immunology (cancer immunology; cancer immunotherapy; cell therapy; molecular cell biology, hematology and medical oncology)

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Papers 【 Display / hide 】

  • Gene editing technology to improve antitumor T-cell functions in adoptive immunotherapy

    Ito Y., Inoue S., Kagoya Y.

    Inflammation and Regeneration （Inflammation and Regeneration)  44 （ 1 ）  2024.12

    Last author, Corresponding author, Accepted

    　View Summary

    Adoptive immunotherapy, in which tumor-reactive T cells are prepared in vitro for adoptive transfer to the patient, can induce an objective clinical response in specific types of cancer. In particular, chimeric antigen receptor (CAR)-redirected T-cell therapy has shown robust responses in hematologic malignancies. However, its efficacy against most of the other tumors is still insufficient, which remains an unmet medical need. Accumulating evidence suggests that modifying specific genes can enhance antitumor T-cell properties. Epigenetic factors have been particularly implicated in the remodeling of T-cell functions, including changes to dysfunctional states such as terminal differentiation and exhaustion. Genetic ablation of key epigenetic molecules prevents the dysfunctional reprogramming of T cells and preserves their functional properties. Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-based gene editing is a valuable tool to enable efficient and specific gene editing in cultured T cells. A number of studies have already identified promising targets to improve the therapeutic efficacy of CAR-T cells using genome-wide or focused CRISPR screening. In this review, we will present recent representative findings on molecular insights into T-cell dysfunction and how genetic modification contributes to overcoming it. We will also discuss several technical advances to achieve efficient gene modification using the CRISPR and other novel platforms.

  • Cytokine signaling in chimeric antigen receptor T-cell therapy

    Yuki Kagoya

    International Immunology （Oxford University Press (OUP))  36 （ 2 ） 49 - 56 2024.02

    Lead author, Last author, Corresponding author, Accepted,  ISSN  09538178

    　View Summary

    Abstract

    Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.

  • Introduction: Synthetic Biology for Cancer Immunology Special Issue

    Kagoya Y.

    International Immunology （International Immunology)  36 （ 2 ） 45 - 48 2024.02

    Last author, Corresponding author, Accepted,  ISSN  09538178

  • AKT2 inhibition accelerates the acquisition of phagocytic ability in induced pluripotent stem cell–derived neutrophils

    Hino T., Nakahara F., Miyauchi M., Ito Y., Masamoto Y., Morita K., Kagoya Y., Kojima H., Kurokawa M.

    Experimental Hematology （Experimental Hematology)  130 2024.02

    Last author, Corresponding author, Accepted,  ISSN  0301472X

    　View Summary

    Neutrophils are key components of the immune system that inhibit bacterial infections. Systemic bacterial infections can cause lethal conditions, especially in patients with neutropenia associated with chemotherapy or other systemic illnesses; hence, early detection of the symptoms and prompt management are crucial in such cases. Previously, we established expandable engineered neutrophil-primed progenitors (NeuPs-XL) using human-induced pluripotent stem cells (iPSCs), which can produce neutrophil-like cells at a clinically suitable scale within 4 days of inducing myeloid differentiation. In this study, using small-molecule compound-based screening, we detected that MK-2206, a selective pan-AKT inhibitor, can accelerate this differentiation process, promote phagocytic ability in neutrophils, and enhance cytokine and chemokine expression in response to lipopolysaccharides. The inhibition of AKT2has been identified as the key mechanism underlying this acceleration. These results can make a substantial contribution to the development of strategies for the prompt production of clinically applicable iPSC-derived neutrophils, which can potentially lead to the management of severe infections associated with life-threatening neutropenia and the effective treatment of related health conditions in the future.

  • Epigenetic profiles guide improved CRISPR/Cas9-mediated gene knockout in human T cells

    Yusuke Ito, Satoshi Inoue, Takahiro Nakashima, Haosong Zhang, Yang Li, Hitomi Kasuya, Tetsuya Matsukawa, Zhiwen Wu, Toshiaki Yoshikawa, Mirei Kataoka, Tetsuo Ishikawa, Yuki Kagoya

    Nucleic Acids Research （Oxford University Press (OUP))  52 （ 1 ） 141 - 153 2024.01

    Last author, Corresponding author, Accepted,  ISSN  0305-1048

    　View Summary

    Abstract

    Genetic modification of specific genes is emerging as a useful tool to enhance the functions of antitumor T cells in adoptive immunotherapy. Current advances in CRISPR/Cas9 technology enable gene knockout during in vitro preparation of infused T-cell products through transient transfection of a Cas9-guide RNA (gRNA) ribonucleoprotein complex. However, selecting optimal gRNAs remains a major challenge for efficient gene ablation. Although multiple in silico tools to predict the targeting efficiency have been developed, their performance has not been validated in cultured human T cells. Here, we explored a strategy to select optimal gRNAs using our pooled data on CRISPR/Cas9-mediated gene knockout in human T cells. The currently available prediction tools alone were insufficient to accurately predict the indel percentage in T cells. We used data on the epigenetic profiles of cultured T cells obtained from transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Combining the epigenetic information with sequence-based prediction tools significantly improved the gene-editing efficiency. We further demonstrate that epigenetically closed regions can be targeted by designing two gRNAs in adjacent regions. Finally, we demonstrate that the gene-editing efficiency of unstimulated T cells can be enhanced through pretreatment with IL-7. These findings enable more efficient gene editing in human T cells.

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 血液がんを標的としたCAR-T細胞療法の現状と課題

    籠谷 勇紀

    炎症と免疫（先端医学社） 31 ( 4 ) 283 - 288 2023.07

  • 多発性骨髄腫に対するCAR-T細胞療法の研究開発動向

    籠谷 勇紀

    血液内科（科学評論社） 86 ( 5 ) 676 - 681 2023.05

  • キメラ抗原受容体遺伝子改変T細胞療法の改良

    籠谷 勇紀

    腫瘍内科（科学評論社） 31 ( 4 ) 462 - 467 2023.04

  • Introduction: Redefining T-cell Exhaustion Special Issue

    Kagoya Y., Togashi Y.

    International Immunology (International Immunology)  34 ( 11 ) 545 - 546 2022.11

    ISSN  09538178

  • Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

    Yusuke Ito, Yuki Kagoya

    Cancer Science 113 ( 11 ) 3664 - 3671 2022.11

    Corresponding author

    　View Summary

    Recent advancements in cancer immunotherapy, such as chimeric antigen receptor (CAR)-engineered T cell therapy and immune checkpoint therapy, have significantly improved the clinical outcomes of patients with several types of cancer. To broaden its applicability further and induce durable therapeutic efficacy, it is imperative to understand how antitumor T cells elicit cytotoxic functions, survive as memory T cells, or are impaired in their effector functions (exhausted) at the molecular level. T cell properties are regulated by their gene expression profiles, which are further controlled by epigenetic architectures, such as DNA methylation and histone modifications. Multiple studies have elucidated specific epigenetic genes associated with T-cell phenotypic changes. Conversely, exogenous modification of these key epigenetic factors can significantly alter T cell functions by extensively altering the transcription network, which can be applied in cancer immunotherapy by improving T cell persistence or augmenting effector functions. As CAR-T cell therapy involves a genetic engineering step during the preparation of the infusion products, it would be a feasible strategy to additionally modulate specific epigenetic genes in CAR-T cells to improve their quality. Here, we review recent studies investigating how individual epigenetic factors play a crucial role in T-cell biology. We further discuss future directions to integrate these findings for optimal cancer immunotherapy.

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Presentations 【 Display / hide 】

  • 合成生物学的アプローチによる がん免疫療法の進化

    籠谷 勇紀

    千里ライフサイエンスセミナーV3, 

    2023.09
    , 

    Oral presentation (invited, special)

  • Development of next-generation CAR-T cell therapy

    Yuki Kagoya

    第6回バイオ医薬EXPO, 

    2022.07
    , 

    Oral presentation (invited, special)

  • CAR-T 細胞療法の適用拡大に向けた研究開発

    籠谷 勇紀

    第7回日本がんサポーティブケア学会学術集会, 

    2022.06
    , 

    Oral presentation (invited, special)

  • エピジェネティクス改変による長期生存型CAR-T細胞の製造

    籠谷 勇紀

    第14回日本血液疾患免疫療法学会, 

    2022.06
    , 

    Oral presentation (invited, special)

  • エピジェネティクス修飾によるCAR-T細胞の改良

    籠谷 勇紀

    第3回東京理科大学総合研究院合成生物学研究部門シンポジウム, 

    2022.03
    , 

    Oral presentation (invited, special)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Development of CAR-NK cell therapy with durable response through genetic manipulation

    2023.04
    -
    2026.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

  • The determination of T-cell fate by different tumor antigens and prevention of post-operative recurrence of lung cancer

    2022.04
    -
    2025.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

  • Development of a combinatorial approach of antibody therapeutics and adoptive immunotherapy for cancer

    2021.07
    -
    2023.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), No Setting

    　View Summary

    キメラ抗原受容体（CAR）導入T細胞は抗原特異的で高い細胞傷害効果を有するが、がん組織内における疲弊誘導などでそのエフェクター効果が減弱すること、及びがん細胞側の標的抗原の喪失などによる免疫逃避機構が働くことが問題である。
    本研究ではCARを通じたエフェクター効果のみならず、CAR-T細胞から、例えば二重特異性抗体などの抗体医薬品を遺伝子レベルで製造・分泌させることで、さらに細胞傷害効果を高めることを目指している。今年度は特定の標的抗原に注目して、分泌に用いる抗体の遺伝子配列について、主にシグナルペプチド、リンカー配列の検討を行った。標的抗原を発現するがん細胞株との共培養の実験系で、がん細胞に対する細胞傷害効果の誘導、培養上清中への薬剤の分泌濃度などの観点から、適した配列を決定した。同分子は抗原を発現しない細胞には作用せず、抗原特異性が付与されていることを確認した。また次年度以降に用いるマウス腫瘍モデルの確立を行った。免疫不全マウス（NSGマウス）に腫瘍細胞株を投与した上で、ヒトCAR-T細胞を輸注する実験系で、腫瘍の増生を抑制できることを確認した。さらに腫瘍量やCART細胞の投与量を調整してCART細胞のみでは腫瘍増生を制御できないプロトコールを設定した。
    次年度以降は複数の標的抗原を検討しながら、in vivoにおけるマウス腫瘍モデルで本治療システムが通常のCAR-T細胞と比較して優れた抗腫瘍効果を誘導できることを示す。同時に他臓器に対する毒性などを検証することで、特異性（安全性）の確認を行う。

  • Generation of long-surviving antitumor T cells by genetic modification for optimal adoptive immunotherapy

    2020.04
    -
    2023.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

    　View Summary

    本研究では、抗腫瘍T細胞の長期生存能を高めるために、T細胞性リンパ腫細胞で変異が報告されている遺伝子群に着目して抗腫瘍T細胞に遺伝子導入を行い、その機能解析、具体的には細胞増殖能、サイトカイン分泌、細胞傷害活性などの評価を通じて、持続的な抗腫瘍効果の改善に寄与する遺伝子修飾標的を同定することを目標としている。
    本年度は、これまでの探索から同定していたがん抑制遺伝子PRDM1のノックアウトによるキメラ抗原受容体(CAR)-T細胞、及び腫瘍浸潤T細胞 (TIL)の機能改善について、さらに解析を進めた。PRDM1をCRISPR/Cas9技術を用いて遺伝子レベルでノックアウトしたCAR-T細胞は、コントロールと比較して生体内における長期生存能に優れ、その結果として有意に治療効果を改善させることを、異なる標的抗原を標的とした複数のマウス腫瘍モデルにおいて示した。特に現在のところ有効な治療効果が得られていない固形がんに対するCAR-T細胞においても、同様に長期生存能の獲得が見られることを示した。その際に、生体内に残存するPRDM1ノックアウトCAR-T細胞が未分化メモリー形質を有意に維持していることも確認した。またTILについては、主に肺癌、婦人科腫瘍検体から採取した検体について、PRDM1ノックアウトの効果を検証した。いずれの検体でも末梢血T細胞と比較して終末分化がより進行していたが、PRDM1ノックアウトにより、一部のメモリー形質の再獲得が起こり、サイトカイン分泌能が改善することを確認した。これらの研究成果は学術論文として受理された (Yoshikawa et al. Blood 2022)。

  • Development of a chimeric synthetic receptor to suppress T cell exhaustion for use in adoptive cancer immunotherapy

    2019.06
    -
    2021.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Kagoya Yuki, Grant-in-Aid for Challenging Research (Exploratory), No Setting

    　View Summary

    The overarching goal of this study is to enhance therapeutic efficacy of adoptive cancer immunotherapy, in which tumor antigen-specific T cells are prepared in vitro and infused into a patient. To suppress T cell exhaustion and provide long-lived potential in antitumor T cells, we developed an artificial receptor that blocks PD1 signaling as well as activates cytokine signaling. The artificial receptor-expressing chimeric antigen receptor (CAR)-engineered T cells showed increased STAT5 phosphorylation and accomplished superior proliferation upon antigen stimulation. Moreover, the artificial receptor-transduced CAR-T cells produced more cytokines when cultured with PDL1-positive tumor cells. These results demonstrate that the newly developed receptor provides T cells with resistance to exhaustion and long-surviving capacity.

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Courses Taught 【 Display / hide 】

  • ADVANCED MEDICAL RESEARCH

    2024

  • INTEGRATION OF BASIC SCIENCE AND CLINICAL MEDICINE

    2024

  • IMMUNOLOGY

    2024

  • CASE STUDY

    2024

  • ADVANCED MEDICAL RESEARCH: SEMINAR

    2024

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