Development of CRISPR/HDR genome editing technology in primary T cells for improved immunotherapy

• Project/Area Number: 17K07212
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Chiba University
• Principal Investigator: OUCHI YASUO 千葉大学, 大学院医学研究院, 特任助教 (70553858)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ゲノム編集 / T細胞 / がん免疫療法 / 免疫細胞療法 / CRISPR/Cas9 / 免疫学

Outline of Final Research Achievements

Recently, immunotherapies have led to the successful development of novel treatments for cancer, primarily by two strategies, immunologic checkpoint blockade therapy, and adoptive T-cell therapy. Although these immunotherapies have shown promising efficacy in the treatment of cancer, there remain considerable difficulties. In this study, to develop the clinically applicable methodology for the immunotherapies using genome-edited T cells, we aim to develop the technology that allows the one-step generation of antigen-specific T cells using non-viral strategy. From the results obtained in this study, we developed a novel nanoparticle carrying genome editing tool for the primary mouse T cells. This technology allows a novel and easy-to-use methodology to generate the genome-edited T cells for use in clinical settings that have been previously impossible.

Academic Significance and Societal Importance of the Research Achievements

近年、免疫チェックポイント阻害剤、ゲノム編集T細胞、がん抗原特異的TCRまたはキメラ抗原受容体(CAR)遺伝子導入T細胞を用いたがん免疫療法は第四の治療法として注目されている。しかし、ゲノム編集技術を用いた免疫細胞療法は国外では臨床試験が進んでいるものの、数多くの技術的な問題を抱えており、幅広い臨床応用は難しい状況である。本研究課題で開発したナノ粒子を利用したゲノム編集技術は従来の遺伝子導入試薬では不可能であった初代T細胞に対する簡便な遺伝子導入およびゲノム編集を可能にする技術である。今後、ゲノム編集T細胞を用いた免疫細胞療法の汎用化において重要なツールになることが期待できる。

Research Products

• [Int'l Joint Research] Salk Institute for Biological Studies/University of California San Francisco(米国)
• [Int'l Joint Research] Nanyang Technological University(シンガポール)
• [Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells (2018)
  • Author(s): Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4231-4231
  • DOI: 10.1038/s41467-018-06468-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of long-term intake of a yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 on mice (2018)
  • Author(s): Usui Yuki、Kimura Yasumasa、Satoh Takeshi、Takemura Naoki、Ouchi Yasuo、Ohmiya Hiroko、Kobayashi Kyosuke、Suzuki Hiromi、Koyama Satomi、Hagiwara Satoko、Tanaka Hirotoshi、Imoto Seiya、Eberl G?rard、Asami Yukio、Fujimoto Kosuke、Uematsu Satoshi
  • Journal Title: International Immunology Volume: 30 Issue: 7 Pages: 319-331
  • DOI: 10.1093/intimm/dxy035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of tumor antigen-specific murine CD8+ T cells with enhanced anti-tumor activity via highly efficient CRISPR/Cas9 genome editing (2018)
  • Author(s): Ouchi Y, Patil A, Tamura Y, Nishimasu H, Negishi A, Paul SK, Takemura N, Satoh T, Kimura Y, Kurachi M, Nureki O, Nakai K, Kiyono H, Uematsu S.
  • Journal Title: International Immunology Volume: 30 Issue: 4 Pages: 141-154
  • DOI: 10.1093/intimm/dxy006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Generation of tumor-specific CD8+ T-cells via highly efficient CRISPR/Cas9 genome editing (2017)
  • Author(s): Yasuo Ouchi, Ashwini Patil, Hiroshi Nishimasu
  • Organizer: XVI KI Cancer-StratCan retreat
• [Presentation] Generation of tumor-specific cytotoxic T cells via highly efficient CRISPR/Cas9 genome editing (2017)
  • Author(s): Yasuo Ouchi, Ashwini Patil, Hiroshi Nishimasu, Osamu Nureki, Kenta Nakai, Satoshi Uematsu
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [Presentation] Generation of tumor-specific cytotoxic T cells via highly efficient CRISPR/Cas9 genome editing (2017)
  • Author(s): Yasuo Ouchi, Ashwini Patil, Hiroshi Nishimasu, Osamu Nureki, Kenta Nakai, Satoshi Uematsu
  • Organizer: 第46回 日本免疫学会学術集会
  • Int'l Joint Research