TCR sequencing of tumor infiltrating T cells using iPS cell technology

• Project/Area Number: 17K19696
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Nagoya University
• Principal Investigator: Naoe Yoshinori 名古屋大学, 医学系研究科, 特任准教授 (50392048)
• Co-Investigator(Kenkyū-buntansha): 粕谷 英樹 名古屋大学, 医学系研究科, 教授 (00402636)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 細胞障害性T細胞 / iPS細胞 / 癌免疫 / T細胞 / 癌抗原 / iPS / T細胞レセプター / がん抗原

Outline of Final Research Achievements

By collecting tumor-specific cytotoxic T cells infiltrating the mouse tumor and introducing Yamanaka factor, it was possible to obtain a cell population that proliferates without anti-CD3 antibody stimulation. These cells were judged as iPS cells because they proliferated without TCR stimulation. In addition, we confirmed a gene rearrangement of the TCRb in all the proliferating cells examined. From the above, it was suggested that cells proliferating without anti-CD3 stimulation are derived from T cells. In addition, we tried to establish iPS cells using human peripheral cytotoxic T cells, but the establishment efficiency was low. In the future, we will investigate culture conditions and try to improve the establishment efficiency.

Academic Significance and Societal Importance of the Research Achievements

本研究により、腫瘍に浸潤したT細胞にin vitroで山中因子を導入しiPS細胞の樹立に成功した。このことから、iPS細胞化したT細胞は無限増殖能を獲得することにより、個々のT細胞のクローニングが容易となり、腫瘍に浸潤した個々のT細胞のTCRを同定することが可能となった。この技術を利用することにより、新規がん抗原ならびにがん抗原を認識するTCRの探索研究が進むと考えられる。

Research Products

• [Journal Article] A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer (2018)
  • Author(s): Hirooka Yoshiki、Kasuya Hideki、Ishikawa Takuya、Kawashima Hiroki、Ohno Eizaburo、Villalobos Itzel B.、Naoe Yoshinori、Ichinose Toru、Koyama Nobuto、Tanaka Maki、Kodera Yasuhiro、Goto Hidemi
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 596-596
  • DOI: 10.1186/s12885-018-4453-z
  • Peer Reviewed / Open Access
• [Journal Article] The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers (2018)
  • Author(s): Eissa Ibrahim、Bustos-Villalobos Itzel、Ichinose Toru、Matsumura Shigeru、Naoe Yoshinori、Miyajima Noriyuki、Morimoto Daishi、Mukoyama Nobuaki、Zhiwen Wu、Tanaka Maki、Hasegawa Hitoki、Sumigama Seiji、Aleksic Branko、Kodera Yasuhiro、Kasuya Hideki
  • Journal Title: Cancers Volume: 10 Issue: 10 Pages: 356-356
  • DOI: 10.3390/cancers10100356
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials. (2017)
  • Author(s): Eissa IR, Naoe Y, Bustos-Villalobos I, Ichinose T, Tanaka M, Zhiwen W, Mukoyama N, Morimoto T, Miyajima N, Hitoki H, Sumigama S, Aleksic B, Kodera Y, Kasuya H.
  • Journal Title: Front Oncol Volume: 7 Pages: 147-147
  • DOI: 10.3389/fonc.2017.00149
  • Peer Reviewed / Open Access
• [Journal Article] Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes. (2017)
  • Author(s): Kojo S, Tanaka H, Endo TA, Muroi S, Liu Y, Seo W, Tenno M, Kakugawa K, Naoe Y, Nair K, Moro K, Katsuragi Y, Kanai A, Inaba T, Egawa T, Venkatesh B, Minoda A, Kominami R, Taniuchi I.
  • Journal Title: Nat Commun. Volume: 8 Issue: 1 Pages: 702-702
  • DOI: 10.1038/s41467-017-00768-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Combination therapy of oncolytic HSV HF10 and immune checkpoint inhibitor (2018)
  • Author(s): H Kasuya, Y Naoe, S Matsumura, I Bustos, T Ichinose, I Eissa, W Zhiwen, N Miyajima, D Morimoto, M Tanaka
  • Organizer: International Oncolytic Virus Conference
  • Int'l Joint Research
• [Presentation] Does the expression level of STING correlate with susceptibility to oncolytic virus HF10 in human pancreatic cell lines? (2018)
  • Author(s): Daishi Morimoto, Yoshinori Naoe, Shigeru Matsumura, Toru Ichinose, Ibrahim Eissa, Itzel Bustos, Noriyuki Miyajima, Nobuaki Mukoyama, Wu Zhiwen, Maki Tanaka, Yasuhiro Kodera, Hideki Kasuya
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
• [Presentation] Involvement of cGAS and STING in sensitivity to oncolytic virus HF10 in breast cancer cell lines (2018)
  • Author(s): Noriyuki Miyajima, Yoshinori Naoe, Shigeru Matsumura, Itzel Bustos, Toru Ichinose, Ibrahim Eissa, Wu Zhiwen, Nobuaki Mukoyama, Daishi Morimoto, Maki Tanaka, Hideki Kasuya
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
• [Presentation] The synergistic effect of the combination therapy of PD-L1 immune checkpoint inhibitor and oncolytic herpes simplex virus HF10 (2018)
  • Author(s): Nobuaki Mukoyama, Ibrahim Eissa, Yoshinori Naoe, Toru Ichinose, Shigeru Matsumura, Itzel Bustos, Wu Zhiwen, Noriyuki Miyajima, Daishi Morimoto, Maki Tanaka, Yasushi Fujimoto, Michihiko Sone, Yasuhiro Kodera, Hideki Kasuya
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
• [Presentation] Final total Data of Clinical trial using HF10 with Gemcitabine and Erlotinib against Unresectable Pancreatic Cancer (2018)
  • Author(s): Hideki Kasuya, Yoshiki Hirooka, Yoshinori Naoe, Shigeru Matsumura, Itzel Bustos, Toru Ichinose, Ibrahim Eissa, Wu Zhiwen, Nobuaki Mukoyama, Noriyuki Miyajima, Daishi Morimoto, Hidemi Goto, Maki Tanaka
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
• [Presentation] STING is dispensable for low susceptibility to C-REV(HF10) in pancreatic cancer cell lines (2018)
  • Author(s): Shigeru Matsumura, Daishi Morimoto, Yoshinori Naoe, Toru Ichinose, Maki Tanaka, Yasuhiro Kodera, Hideki Kasuya
  • Organizer: 4th ONCOLYTIC VIROTHERAPY Summit
• [Presentation] Clinical trial using HF10 with Gemcitabine and Erlotinib for 9 patients of Unresectable pancreatic cancer (2018)
  • Author(s): Hideki Kasuya, Yoshiki Hirooka, Yoshinori Naoe, Shigeru Matsumura, Itzel Bustos, Toru Ichinose, Ibrahim Eissa, Wu Zhiwen, Nobuaki Mukoyama, Noriyuki Miyajima, Daishi Morimoto, Hidemi Goto, Maki Tanaka
  • Organizer: 第56回日本癌治療学会学術集会
• [Presentation] The synergistic effect of the combination therapy of PD-L1 immune checkpoint inhibitor and oncolytic herpes simplex virus Canerpaturev(C-REV) (2018)
  • Author(s): Yoshinori Naoe, Nobuaki Mukoyama, Ibrahim Eissa, Toru Ichinose, Shigeru Matsumura, Itzel Bustos, Wu Zhiwen, Noriyuki Miyajima, Daishi Morimoto, Maki Tanaka, Yasushi Fujimoto, Michihiko Sone, Yasuhiro Kodera, Hideki Kasuya
  • Organizer: 第56回日本癌治療学会学術集会
• [Presentation] ヒト膵癌異種移植モデルにおけるnab-Paclitaxel（nab-PTX）と腫瘍溶解性単純ヘルペスウイルスHF10 との併用療法 (2017)
  • Author(s): 森本 大士, 直江 吉則, 一ノ瀬 亨, Bustos Itzel, 神田 光郎, 丹羽 由紀子, 岩田 直樹, 林 真路, 小林 大介, 田中 千恵, 山田 豪, 中山 吾郎, 杉本 博行, 小池 聖彦, 藤原 道隆, 藤井 努, 田中 舞紀, 粕谷 英樹, 小寺 泰弘
  • Organizer: 第117 回日本外科学会定期学術集会
• [Presentation] ヒト大腸がんモデルにおけるセツキシマブとの併用による腫瘍溶解性ウイルスHF10 の抗腫瘍効果 (2017)
  • Author(s): 呉 智聞, 一ノ瀬 亨, 駱 晨虹, 直江 吉則, イッツェル・ブストス・ビジャロボス, 山田 豪, 藤井 努, 杉本 博行, 森本 大士, 向山 宣昭, 小寺 泰弘, 田中 舞紀, 粕谷 英樹
  • Organizer: 第117 回日本外科学会定期学術集会
• [Presentation] HF10 ウイルス療法におけるin situ vaccination効果についての検討 (2017)
  • Author(s): 粕谷 英樹, 直江 吉則, Bustos Itzel, 一ノ瀬 亨, 森本 大士, 向山 宣昭, 呉 智聞, 藤井 努, 小寺 泰弘, 田中 舞紀
  • Organizer: 第117 回日本外科学会定期学術集会
• [Presentation] Combination therapy of oncolytic herpes virus and anti-angiogenesis agent (bevacizumab) against human gastric cancer xenograft (2017)
  • Author(s): H. Kasuya, G. Tan, C. Luo, T. Ichinose, I. Bustos, Y. Naoe
  • Organizer: EACR-AACR-SIC Special Conference 2017
• [Presentation] Combination therapy of PD-L1 immune checkpoint inhibitor and oncolytic herpes simplex virus HF10 (2017)
  • Author(s): Mukoyama N, Naoe Y, Ichinose T, Nassr E. I. R, Luo C, Villalobos I. B, Zhiwen W, Miyajima N, Morimoto D, Tanaka M, Fujimoto Y, Sone M, Kodera Y, Kasuya H.
  • Organizer: 第23回日本遺伝子細胞治療学会学術集会
• [Presentation] Combination therapy against human pancreatic cancer with oncolytic herpes virus HF10 and abraxane (2017)
  • Author(s): Wu Z, Ichinose T, Luo C, Naoe Y, Villalobos I. B, Yamada S, Fujii T, Sugimoto H, Miyajima N, Morimoto D, Mukoyama N, Nishikawa Y, Koide U, Kuwahara T, Kodera Y, Tanaka M, Kasuya H.
  • Organizer: 第23回日本遺伝子細胞治療学会学術集会
• [Presentation] Systemic therapeutic potential of oncolytic herpes simplex virus HF10 adsorbed on antigen-specific lymphocytes (2017)
  • Author(s): Ichinose T, Naoe Y, Nassr E. I. R, Luo C, Villalobos I. B, Zhiwen W, Mukoyama N, Miyajima N, Morimoto D, Yamada S, Fujii T, Sugimoto H, Tanaka M, Kodera Y, Kasuya H.,
  • Organizer: 第23回日本遺伝子細胞治療学会学術集会
• [Presentation] Clinical trial data using HF10, oncolytic herpes simplex virus (2017)
  • Author(s): Kasuya H, Ichinose T, Naoe Y, Villalobos I. B, Nassr E. I. R, Luo C, Zhiwen W, Mukoyama N, Miyajima N, Morimoto D, Hirooka Y, Goto H, Tanaka M.
  • Organizer: 第23回日本遺伝子細胞治療学会学術集会
• [Presentation] COMBINATION THERAPY AGAINST HUMAN COLORECTAL CANCER WITH THE EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITOR CETUXIMAB AND ONCOLYTIC HERPES SIMPLEX VIRUS HF10 (2017)
  • Author(s): 呉 智聞, 一ノ瀬 亨, 駱 晨虹, 直江 吉則, ヴィラロボス イッツェル・バストス, 山田 豪, 杉本 博行, 宮嶋 則行, 森本 大士, 向山 宣昭, 西川 洋子, 小出 悠介, 小寺 泰弘, 田中 舞紀, 粕谷 英樹
  • Organizer: 第55回日本癌治療学会学術集会
• [Presentation] Combination therapy of PD-L1 immune checkpoint inhibitor and oncolytic herpes simplex virus HF10 (2017)
  • Author(s): 森本 大士, 直江 吉則, 向山 宜明, 一ノ瀬 亨, Itzel Bustos Villalobos, 神田 光郎, 丹羽 由紀子, 岩田 直樹, 林 真路, 小林 大介, 田中 千恵, 中山 吾郎, 山田 豪, 杉本 博行, 小池 聖彦, 藤原 道隆, 田中 舞紀, 藤本 保志, 粕谷 英樹, 小寺 泰
  • Organizer: 第28回日本消化器癌発生学会総会
• [Presentation] 腫瘍溶解性単純ヘルペスウイルスHF10と免疫チェックポイント阻害剤の併用 (2017)
  • Author(s): 森本 大士, 直江 吉則, 向山 宜明, 宮嶋 則行, Ibrahim Ragab Eissa, 一ノ瀬 亨, Itzel Bustos-Villalobos, 山田 豪, 田中 舞紀, 藤本 保志, 小寺 泰弘, 粕谷 英樹
  • Organizer: 第51回制癌剤適応研究会
• [Book] 遺伝子医学MOOK 31号 がん免疫療法 - What's now and what's next? 第2章の4の3) 腫瘍溶解性ウイルスHF10による再発乳がん多発結節症例, 切除不能進行膵がん症例に対する臨床研究 (2017)
  • Author(s): 粕谷 英樹, 直江 吉則, 一ノ瀬 亨, 廣岡 芳樹, 後藤 秀実, 田中 舞紀
  • Total Pages: 294
  • Publisher: (株)メディカル ドゥ
• [Remarks] 名古屋大学大学院医学系研究科 癌免疫治療研究室
  • URL: https://www.med.nagoya-u.ac.jp/intlexch/cancerimmuno/www/index.html