Development of evolutional gene modified T cell transfusion therapy using novel and self-developed measles viral vector

• Project/Area Number: 17H01547
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: TANI Kenzaburo 東京大学, 医科学研究所, 特任教授 (00183864)
• Co-Investigator(Kenkyū-buntansha): 竹田 誠 国立感染症研究所, ウイルス第三部, 部長 (40311401)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥41,990,000 (Direct Cost: ¥32,300,000、Indirect Cost: ¥9,690,000); Fiscal Year 2019: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000); Fiscal Year 2018: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000); Fiscal Year 2017: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
• Keywords: 麻疹ウイルスベクター / 遺伝子挿入 / キメラ抗原T細胞療法 / ナイーブT細胞 / 抗腫瘍効果 / Magnetタンパク / メチオニン分解酵素 / T細胞 / プラスミド / ウイルス / 遺伝子 / 応用微生物 / 免疫学 / がん / ウイルスベクター / 遺伝子治療 / T細胞療法

Outline of Final Research Achievements

Our newly developed measles virus vector (MVV) is a novel and nonintegrative viral vector which proliferates cytoplasmically without inducing any genome toxicity in gene-transduced cells and can express target genes efficiently and safely for limited time. In this project we successfully could establish low immunogenic MVV for the purpose of clinically translatable effective chimeric antigen receptor (CAR)-T cell therapy. Furthermore, we developed novel photocontrollable measles virus proliferating methods using Magnet protein gene and tumor-specific killing methods using methioninase gene. Based on these current results, we will develop a novel, effective and safe second generation CAR-T cell therapy targeting solid tumors in our next project.

Academic Significance and Societal Importance of the Research Achievements

麻疹ウイルスベクター（MVV）は我々が独自開発し、世界で初めて高安全性のヒト人工多能性幹（hiPS）細胞樹立に成功すると共に、生体内での抗腫瘍免疫誘導に極めて重要であると考えられるナイーブT細胞に高効率で遺伝子導入できることを初めて発見した。本研究では臨床応用を前提にMVVの抗原性の減弱、光によるベクター増幅制御の可能化、メチオニン分解酵素遺伝子搭載の可能化、に関する技術開発を行った。本研究の学術的意義および新規性は高く、本方法の確立により、より効果的な難治性固形腫瘍に対する治療法の開発が可能になることが期待できることから、社会的貢献度も極めて高いものと考えられる。

Research Products

• [Journal Article] Safe Use of Nivolumab in a Patient with Epipharyngeal Carcinoma and Preexisting Ulcerative Colitis: A Histologically Proven Case Report (2020)
  • Author(s): Hijikata Yasuki、Matsubara Yasuo、Ota Yasunori、Lim Lay Ahyoung、Tani Kenzaburo、Hirata Yoshihiro、Yotsuyanagi Hiroshi
  • Journal Title: Internal Medicine Volume: 59 Issue: 8 Pages: 1105-1109
  • DOI: 10.2169/internalmedicine.3901-19
  • NAID: 130007831684
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-04-15
  • Peer Reviewed / Open Access
• [Journal Article] Successful clinical sequencing by molecular tumor board in an elderly patient with refractory Sezary syndrome (2020)
  • Author(s): Hijikata K, Yokoyama K (co-1st and co-corresponding author), Yokoyama N, Matsubara Y, Shimizu E, Nakashima M, Yamagishi M, Ota Y, Lim L, Yamaguchi R, Ito M, Tanaka Y, Denda T, Tani K, Yotsuyanagi H, Imoto S, Miyano S, Uchimaru K, Tojo A.
  • Journal Title: JCO Precis Oncol Volume: 4 Issue: 4 Pages: 534-560
  • DOI: 10.1200/po.19.00254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A pilot study to establish human T‐cell leukemia virus type 1 (HTLV‐1) carrier model using common marmoset ( Callithrix jacchus ) (2020)
  • Author(s): Hirose Lisa、Hiramoto Takafumi、Tian Yamin、Kohara Hiroshi、Kobayashi Seiichiro、Nagai Etsuko、Denda Tamami、Tanaka Yukihisa、Ota Yasunori、Jiyuan Liao、Miyamoto Shohei、Miura Yoshie、Hijikata Yasuki、Soda Yasushi、Inoue Takashi、Okahara Norio、Itoh Toshio、Sasaki Erika、Tojo Arinobu、Uchimaru Kaoru、Tani Kenzaburo
  • Journal Title: Journal of Medical Primatology Volume: 49 Issue: 2 Pages: 86-94
  • DOI: 10.1111/jmp.12454
  • Peer Reviewed / Open Access
• [Journal Article] Non-transmissible MV Vector with Segmented RNA Genome Establishes Different Types of iPSCs from Hematopoietic Cells (2020)
  • Author(s): Hiramoto T、Tahara M、Liao J、Soda Y、Miura Y、Kurita R、Hamana H、Inoue K、Kohara H、Miyamoto S、Hijikata Y、Okano S、Yamaguchi Y、Oda Y、Ichiyanagi K、Toh H、Sasaki H、Kishi H、Ryo A、Muraguchi A、Takeda M、Tani K
  • Journal Title: Molecular Therapy Volume: 28 Issue: 1 Pages: 129-141
  • DOI: 10.1016/j.ymthe.2019.09.007
  • Peer Reviewed / Open Access
• [Journal Article] Photocontrollable mononegaviruses (2019)
  • Author(s): Tahara M, Takishima Y, Miyamoto S, Nakatsu Y, Someya K, Sato M, Tani K, Takeda M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 116 Issue: 24 Pages: 11587-11589
  • DOI: 10.1073/pnas.1906531116
  • Peer Reviewed / Open Access
• [Journal Article] KLF1 Mutation E325K Induces Cell-cycle Arrest in Erythroid Cells Differentiated from Congenital Dyserythropoietic Anemia (CDA) Patient-specific Induced Pluripotent Stem Cells. (2019)
  • Author(s): Kohara H, Utsugisawa T, Sakamoto C, Hirose L, Ogawa Y, Ogura H, Sugawara A, Aoki T, Iwasaki T, Asai T, Doisaki S, Okuno Y, Muramatsu H, Abe T, Kurita R, Miyamoto S, Sakuma T, Shiba M, Yamamoto T, Ohga S, Yoshida K, Ogawa S, Ito E, Kojima S, Kanno H, Tani K.
  • Journal Title: Exp Hematol. Volume: 73 Pages: 25-37
  • DOI: 10.1016/j.exphem.2019.03.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Granulocyte colony-stimulating factor-associated aortitis in the Japanese adverse drug event report database. (2019)
  • Author(s): Oshima Y., Takahashi S., Tani K., Tojo A.
  • Journal Title: Cytokine. Volume: 119 Pages: 47-51
  • DOI: 10.1016/j.cyto.2019.02.013
  • Peer Reviewed / Open Access
• [Journal Article] Extremely low organ toxicity and strong antitumor activity of miR-34-regulated oncolytic coxsackievirus B3. (2019)
  • Author(s): Jia, Y., Miyamoto, S., Soda, Y., Takishima, Y., Sagara, M., Liao, J., Hirose-Yotsuya, L., Hijikata, Y., Miura, Y., Hara, K., Iwanaga, A., Ota, Y., Tani, K.
  • Journal Title: Mol Ther Oncolytics. Volume: 12 Pages: 246-258
  • DOI: 10.1016/j.omto.2019.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Cloning of carrier cells infected with oncolytic adenovirus driven by midkine promoter and biosafety studies (2018)
  • Author(s): Hamada Katsuyuki、Takagi Soichi、Kuboshima Hajime、Shimada Hideaki、Takagi Kazuko、Yasuoka Toshiaki、Matsubara Keiichi、Sassa Yukiko、Furuya Tetsuya、Suzuki Kazuhiko、Uchide Tsuyoshi、Mizutani Tetsuya、Tani Kenzaburo、Itoh Hiroshi、Sugiyama Takashi
  • Journal Title: The Journal of Gene Medicine Volume: 21 Issue: 2-3
  • DOI: 10.1002/jgm.3064
  • Peer Reviewed / Open Access
• [Journal Article] FEAT enhances INSL3 expression in testicular Leydig cells. (2018)
  • Author(s): Li Y, Kobayashi K, Murayama K, Kawahara K, Shima Y, Suzuki A, Tani K, *Takahashi A.
  • Journal Title: Genes Cells Volume: 23 Issue: 11 Pages: 952-962
  • DOI: 10.1111/gtc.12644
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel combination therapy for human oxaliplatin-resistant colorectal cancer using oxaliplatin and coxsackievirus A11. (2018)
  • Author(s): Wang, B., Ogata, H., Takishima, Y., Miyamoto, S., Inoue, H., Kuroda, M., Yamada, K., Hijikata, Y., Murahashi, M., Shimizu, H., Okazaki, T., Nakanishi, Y., Tani, K.
  • Journal Title: Anticancer Res. Volume: 38 Issue: 11 Pages: 6121-6126
  • DOI: 10.21873/anticanres.12963
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors. (2018)
  • Author(s): Hijikata Y, Okazaki T, Tanaka Y, Murahashi M, Yamada Y, Yamada K, Takahashi A, Inoue H, Kishimoto J, Nakanishi Y, Oda Y, Nakamura Y, Tani K
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: e0187878-e0187878
  • DOI: 10.1371/journal.pone.0187878
  • Peer Reviewed / Open Access
• [Journal Article] Pathway-Based Drug Repositioning for Cancers: Computational Prediction and Experimental Validation. (2018)
  • Author(s): Iwata, M., Hirose, L., Kohara, H., Liao, J., Sawada, R., Akiyoshi, S., Tani, K., Yamanishi, Y.
  • Journal Title: J Med Chem. Volume: 61 Issue: 21 Pages: 9583-9595
  • DOI: 10.1021/acs.jmedchem.8b01044
  • Peer Reviewed
• [Journal Article] Current state of therapeutic development for rare cancers in Japan, and proposals for improvement. (2018)
  • Author(s): Kawai A, Goto T, Shibata T, Tani K, Mizutani S, Nishikawa A, Shibata T, Matsumoto S, Nagata K, Narukawa M, Matsui S, Ando M, Toguchida J, Monden M, Heike T, Kimura S, Ueda R.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 5 Pages: 1731-1737
  • DOI: 10.1111/cas.13568
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis (2018)
  • Author(s): Shitaoka Kiyomi、Hamana Hiroshi、Kishi Hiroyuki、Hayakawa Yoshihiro、Kobayashi Eiji、Sukegawa Kenta、Piao Xiuhong、Lyu Fulian、Nagata Takuya、Sugiyama Daisuke、Nishikawa Hiroyoshi、Tanemura Atsushi、Katayama Ichiro、Murahashi Mutsunori、Takamatsu Yasushi、Tani Kenzaburo、Ozawa Tatsuhiko、Muraguchi Atsushi
  • Journal Title: Cancer Immunology Research Volume: 6 Issue: 4 Pages: 378-388
  • DOI: 10.1158/2326-6066.cir-17-0489
  • Peer Reviewed / Open Access
• [Presentation] Novel Viral Oncolytic Therapies for Cancer (2019)
  • Author(s): Tani K
  • Organizer: The 4th TRANSMED-VN Conference
• [Presentation] Clinical translation of novel oncolytic Coxsickievirus B3 targeting solid tumors (2019)
  • Author(s): Tani K
  • Organizer: International Gene and Cell Therapy Symposium IGCT
• [Presentation] 5-ALAを用いた末梢血循環がん細胞の検出法確立にむけたパイロット研究 (2019)
  • Author(s): 廣瀬理沙、小原洋志、相良京、三浦由恵、土方康基、曽田泰、宮本将平、廖紀元、高橋聡、篠崎大、大田泰徳、渡辺恵理、田中徹、中島元夫、木庭幸子、奥山隆平、福原秀雄、井上啓史、並川努、花﨑和弘、谷憲三朗
  • Organizer: 第９回ポルフィリン-ALA学会
• [Presentation] Development of microRNA-regulated oncolytic Coxsackievirus for clinical trial (2019)
  • Author(s): Miyamoto S, Sagara M, Jia Y, Soda Y, Miura Y, Shimizu H, Tani K
  • Organizer: 第25回日本遺伝子細胞治療学会学術集会
• [Presentation] Direct induction of naive-like human induced pluripotent stem cells (iPSCs) by a non-integrating measles virus vector (2019)
  • Author(s): Liao J, Soda Y, Sugawara A, Miura Y, Hiramoto T, Tahara M, Takishima Y, Hijikata Y, Miyamoto S, Takeda M, Tani K
  • Organizer: 第25回日本遺伝子細胞治療学会学術集会
• [Presentation] Measles virus vector is a promising tool for T-cell engineering and establishing naive-like iPSCs (2019)
  • Author(s): Liao J, Soda Y, Sugawara A, Miura Y, Hiramoto T, Tahara M, Takishima Y, Miyamoto S, Hijikata Y, Takeda M, Tani K
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 5-ALAを用いた末梢血循環がん細胞の検出法確立にむけたパイロット研究 (2019)
  • Author(s): 廣瀬理沙、小原洋志、相良京、三浦由恵、石井有美子、土方康基、曽田泰、宮本将平、廖紀元、高橋聡、篠崎大、大田泰徳、渡辺恵理、田中徹、中島元夫、木庭幸子、奥山隆平、福原秀雄、井上啓史、並川努、花﨑和弘、谷憲三朗
  • Organizer: 第６回PDDTフォーラム
• [Presentation] Dual microRNA Engineered Oncolytic Coxsackievirus Virotherapy for Clinical Trial (2019)
  • Author(s): Miyamoto S, Jia Y, Soda Y, Sagara M, Liao J, Hirose L, Hijikata Y, Hara K, Iwanaga A, Tani K
  • Organizer: American Society of Gene and Cell Therapy 22nd Annual Meeting
• [Presentation] Novel microRNA engineered oncolytic virotherapy for clinical trial. (2018)
  • Author(s): Jia Y, Miyamoto S, Hirose L, Sagara M, Takishima Y, Shimizu H, Tani K.
  • Organizer: ASGCT 21st Annual Meeting, USA.
• [Presentation] Evaluation of Non-Integrating RNA Measles Virus Vectors for Reprogramming of Human Hematopoietic Subsets. (2018)
  • Author(s): Liao J, Kohara H, Hiramoto T, Tahara M, Sugawara A, Miura Y, Hirose L, Takishima Y, Miyamoto S, Takeda M, Tani K.
  • Organizer: ASGCT 21st Annual Meeting, USA.
• [Presentation] Pilot study to detect circulating tumor cells in human peripheral blood using 5-aminolevulinic acid. (2018)
  • Author(s): Hirose L, Kohara H, Miura Y, Hijikata Y, Soda Y, Miyamoto S, Liao J, Takahashi S, Shinozaki M, Ota Y, Watanabe E, Tanaka T, Nakajima M, Kiniwa S, Okuyama R, Fukuhara H, Inoue K, Namikawa T, Hanasaki K, Tani K.
  • Organizer: 6th International ALA and Porphyrin Symposium, Shizuoka.
• [Presentation] Efficient Gene Transduction and Reprogramming of Hematopoietic Cells Including T-Cells By Using a Non-Integrating Measles Virus Vector. (2018)
  • Author(s): Liao J, Soda Y, Sugawara A, Miura Y, Hiramoto T, Tahara M, Takishima Y, Hirose L, Hijikata Y, Miyamoto S, Takeda M, Tani K.
  • Organizer: 60th ASH Annual Meeting and Exposition, USA.
• [Presentation] 5-ALAを用いた末梢血循環がん細胞の検出法確立にむけたパイロット研究 (2018)
  • Author(s): 廣瀬理沙、小原洋志、宮本将平、土方康基、高橋聡、篠崎大、田中徹、中島元夫、木庭幸子、奥山隆平、福原秀雄、井上啓史、並川努、花﨑和弘、谷憲三朗.
  • Organizer: 第8回ポルフィリン-ALA学会年会, 東京
• [Presentation] Dysregulated cell-cycle by KLF1 mutation induces cell-cycle arrest in erythroid cells derived from CDA- iPSCs. (2018)
  • Author(s): Hirose L, Kohara H, Utsugisawa T, Ogura H, Sugawara A, Ogawa Y, Sakamoto C, Kanno H, Tani K.
  • Organizer: 第66回日本輸血・細胞治療学会総会，栃木
• [Presentation] Large scale production of novel recombinant coxsacievirus B3 towards human clinical trial. (2018)
  • Author(s): Sagara M, Miyamoto S, Hara K, Miura Y, Hirose L, Takishima Y, Jia Y, Soda Y, Hijikata Y, Iwanaga A, Shimizu H, Tani K.
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会, 東京
• [Presentation] Non-integrating measles virus vector is an outstanding gene transfer tool for establishing iPSCs from human T cells and hematopoietic progenitor cells. (2018)
  • Author(s): Liao J, Soda Y, Sugawara A, Miura Y, Hiramoto T, Kohara H, Hirose L, Takishima Y, Hijikata Y, Miyamoto S, Tahara M, Takeda M, Tani K.
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会, 東京.
• [Presentation] Novel microRNA engineered coxsackievirus B3 for oncolytic virotherapy. (2018)
  • Author(s): Jia Y, Miyamoto S, Hirose L, Sagara M, Takishima Y, Shimizu H, Tani K.
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会, 東京.
• [Presentation] Novel safe and effective oncolytic virotherapy by miRNA-regulation. (2018)
  • Author(s): Jia Y, Miyamoto S, Hirose L, Sagara M, Takishima Y, Shimizu H, Tani K.
  • Organizer: 第77回日本癌学会学術総会, 大阪.
• [Presentation] The investigation of a recombinant coxsackievirus B3 manufacturing process for human clinical trial. (2018)
  • Author(s): Sagara M, Miyamoto S, Hara K, Miura Y, Hirose L, Takishima Y, Jia Y, Soda Y, Hijikata Y, Iwanaga A, Shimizu H, Tani K.
  • Organizer: 第77回日本癌学会学術総会, 大阪.
• [Presentation] Successful establishment of iPSCs from hematopoietic cells with a non-integrating measles virus vector. (2018)
  • Author(s): Liao J, Soda Y, Sugawara A, Miura Y, Hiramoto T, Takishima Y, Hijikata Y, Miyamoto S, Tahara M, Takeda M, Tani K.
  • Organizer: 第10回血液疾患免疫療法学会学術集会, 東京.
• [Presentation] Pilot study to detect circulating tumor cells in human peripheral blood using 5-aminolevulinic acid. (2018)
  • Author(s): Hirose L, Kohara H, Miyamoto S, Hijikata Y, Takahashi S, Shinozaki M, Ota Y, Watanabe E, Tanaka T, Nakajima M, Kiniwa S, Okuyama R, Fukuhara H, Inoue K, Namikawa T, Hanasaki K, Tani K.
  • Organizer: 第80回日本血液学会学術集会, 大阪.
• [Presentation] 5-ALAを用いた末梢血循環がん細胞の検出法確立にむけたパイロット研究 (2018)
  • Author(s): 廣瀬理沙、小原洋志、三浦由恵、土方康基、曽田泰、宮本将平、廖紀元、高橋聡、篠崎大、大田泰徳、渡辺恵理、田中徹、中島元夫、木庭幸子、奥山隆平、福原秀雄、井上啓史、並川努、花﨑和弘、谷憲三朗.
  • Organizer: 第5回先端PDDTフォーラム, 奈良.
• [Patent(Industrial Property Rights)] 鎌状赤血球症の改善及び／又は予防剤 (2019)
  • Inventor(s): 谷憲三朗、曽田泰、廖紀元、宮本将平、河田聡史、富岡基康、児玉健
  • Industrial Property Rights Holder: 谷憲三朗、曽田泰、廖紀元、宮本将平、河田聡史、富岡基康、児玉健
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-170764
  • Filing Date: 2019