KEIO RESEARCHERS INFORMATION SYSTEM

Profile 【 Display / hide 】

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.

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2007.04

  -

  2009.03

  Kanto Rosai Hospital, 内科

• 2013.04

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  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 】

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

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

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

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

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

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Plasma membrane-coated nanoparticles and membrane vesicles to orchestrate multimodal antitumor immunity.

  Yusuke Ito, Hitomi Kasuya, Mirei Kataoka, Noriko Nakamura, Toshiaki Yoshikawa, Takahiro Nakashima, Haosong Zhang, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Chitose Oneyama, Seiichi Ohta, Yuki Kagoya

  Journal for immunotherapy of cancer 13 ( 1 )  2025.01

  Last author, Corresponding author, Accepted

  　View Summary

  BACKGROUND: A number of immunotherapeutic approaches have been developed and are entering the clinic. Bispecific antibodies (BsAbs) are one of these modalities and induce robust efficacy by endogenous T cells in several hematological malignancies. However, most of the treated patients experience only a temporary benefit. Currently available BsAbs provide only anti-CD3 antibody-mediated T-cell stimulation, but not the costimulation or cytokine signaling essential for full T-cell activation. Here, we hypothesized that the simultaneous input of more comprehensive signals would elicit more robust and durable effector T-cell functions. METHODS: We genetically engineered the leukemia cell line K562 to express BsAbs, costimulatory ligands, cytokines, and blocking antibodies against immune checkpoint molecules on the cell surface, from which we obtained plasma membrane fractions by mechanical homogenization and subsequent isolation steps. Plasma membranes were reconstituted on the poly (lactic-co-glycolic acid) surface to generate membrane-coated nanoparticles (NPs). Alternatively, nano-sized membrane vesicles (MVs) were generated by ultrasonic dispersion of the isolated membranes. The antitumor function of NPs and MVs loaded with various immunomodulatory factors was evaluated in vitro and in vivo. RESULTS: Both membrane-coated NPs and MVs induced BsAb-mediated antigen-specific cytotoxic activity in non-specific T cells, with MVs inducing a slightly better response in vivo. Importantly, T-cell activation was elicited only in the presence of target tumor cells, providing a safety advantage for clinical use. NPs and MVs expressing costimulatory molecules (CD80/4-1BBL) and cytokines (interleukin (IL)-7/IL-15) further enhanced effector T-cell function and induced therapeutic efficacy in vivo. In addition, MVs expressing immune checkpoint antibodies and inflammatory cytokines IL-12 and IL-18 induced objective antitumor responses in solid tumor models partly by converting immunosuppressive macrophages to proinflammatory phenotypes and inducing cytotoxic T-cell infiltration into the tumor. Finally, we showed that MVs were also engineered to activate natural killer (NK) cells by loading multiple ligands. MVs loaded with BsAbs, 4-1BBL, IL-15, and IL-21 induced NK-cell cytotoxic activity in an antigen-specific manner. CONCLUSIONS: We developed antitumor NPs and MVs that efficiently induced antitumor immune responses in vivo by simultaneously delivering multiple immunostimulatory signals to endogenous T cells. This platform enables the delivery of desired combinations of antitumor immune signals into T cells and NK cells.

  • Access to Document (DOI)

• Protocol to measure human IL-6 secretion from CAR T cell-primed macrophage and monocyte lineage cells in vitro and in vivo using humanized mice.

  Thao Nguyen, Toshiaki Yoshikawa, Yusuke Ito, Hitomi Kasuya, Takahiro Nakashima, Sachiko Okamoto, Yasunori Amaishi, Haosong Zhang, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya

  STAR protocols 5 ( 4 ) 103423 - 103423 2024.12

  Last author, Corresponding author, Accepted

  　View Summary

  Chimeric antigen receptor (CAR) T cell therapy often causes serious toxicities, such as cytokine release syndrome (CRS), mainly due to interleukin-6 (IL-6) secreted by monocyte lineage cells. Here, we describe a protocol to generate anti-CD19 CAR T cells and quantify human monocyte-derived IL-6 cocultured with CAR T cells and target tumor cells in vitro. We further describe a protocol to generate a humanized mouse model and evaluate CAR T cell-associated plasma IL-6 levels in vivo. For complete details on the use and execution of this protocol, please refer to Yoshikawa et al.1.

  • Access to Document (DOI)

• 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.

  • Access to Document (DOI)

• Current progress of CAR-T-cell therapy for patients with multiple myeloma

  Nakashima T, Kagoya Y

  Int J Hematol 120 ( 1 ) 15 - 22 2024.05

  Last author, Corresponding author, Accepted,  ISSN  09255710

  　View Summary

  Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies.

  • Access to Document (DOI)

• Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells

  Toshiaki Yoshikawa, Yusuke Ito, Zhiwen Wu, Hitomi Kasuya, Takahiro Nakashima, Sachiko Okamoto, Yasunori Amaishi, Haosong Zhang, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya

  Cell Reports Medicine (Elsevier BV)  5 ( 5 ) 101526 - 101526 2024.05

  Last author, Corresponding author, Accepted,  ISSN  2666-3791

  　View Summary

  The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

  • Access to Document (DOI)

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Reviews, Commentaries, etc. 【 Display / hide 】

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

  • Access to Document (DOI)

• 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 】

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 】

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

• Balancing memory and effector T cell function through epigenetic modification

  2024.06

  -

  2026.03

  挑戦的研究（萌芽）, Principal investigator

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

  2023.04

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  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

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  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)。

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Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• ADVANCED MEDICAL RESEARCH

  2025

• ADVANCED MEDICAL RESEARCH

  2025

• ADVANCED MEDICAL RESEARCH: PRACTICE

  2025

• ADVANCED MEDICAL RESEARCH: SEMINAR

  2025

• IMMUNOLOGY

  2025

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