Therapeutic potintial of Tregs transduced with CEA specific CAR in sever asthma

• Project/Area Number: 16K09533
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Mie University
• Principal Investigator: KATO Takuma 三重大学, 医学系研究科, 准教授 (60224515)
• Co-Investigator(Kenkyū-buntansha): 王 立楠 三重大学, 医学系研究科, 特任助教(研究担当) (00589484) ; 宮原 慶裕 三重大学, 医学系研究科, 准教授 (10582083)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: キメラ抗原受容他 / 制御性T細胞 / T細胞輸注療法 / 癌胎児性抗原 / 喘息 / キメラ抗原受容体 / 制御性Ｔ細胞 / Ｔ細胞輸注療法 / 固形がん / GITRシグナル

Outline of Final Research Achievements

Regulatory T cells (Tregs) play an important role not only in immunological self-tolerance but also in various inflammatory diseases. In this study, we explored the possibility that Tregs redirected toward carcinoembryonic antigen (CEA) expressed on lung epithelia have potential to control allergic airway inflammation. Retrovirally transduced Tregs with chimeric antigen receptor (CAR) gene constituting scFv specific to CEA as an ectodomain and signaling domains derived from CD3zeta and CD28 as an endodomain exerted potent regulatory activity in vitro. Using a mouse model of allergic asthma, the effect of adoptively transferred CEA-specific CAR-Tregs on airway inflammation will be examined.

Academic Significance and Societal Importance of the Research Achievements

本研究では、気管支喘息患者の炎症局所、即ち気道上皮に恒常的に発現しているCEAでTregを活性化することで様々な疾患起因アレルゲンに対する過剰免疫応答によって発症する気管支喘息を制御することに特色があり、ステロイドによる炎症抑制作用とは作用機序が異なり、難治性喘息患者に対して有効な新規治療法となり得る。また、免疫抑制は炎症局所に限定し全身性の免疫抑制を伴わないことが期待され、感染症に対する抵抗力を削ぐことが無く、全身的な免疫抑制を伴う治療法に比較して優れた治療法になり得ると考えられる。

Research Products

• [Journal Article] Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. (2018)
  • Author(s): Akahori Y, Wang L, Yoneyama M, Seo N, Okumura S, Miyahara Y, Amaishi Y, Okamoto S, Mineno J, Ikeda H, Maki T, Fujiwara H, Akatsuka Y, Kato T, Shiku H.
  • Journal Title: Blood. 2018 Sep 13;132(11): Volume: 132 Issue: 11 Pages: 1134-1145
  • DOI: 10.1182/blood-2017-08-802926
  • Peer Reviewed / Open Access
• [Journal Article] 腸内細菌とがん治療応答性 (2017)
  • Author(s): 1.加藤琢磨
  • Journal Title: 遺伝子医学MOOK Volume: 31 Pages: 55-59
• [Journal Article] Challenge of ex vivo-stimulated CD4(+)CD25(+) regulatory T cell-mediated alloantigen-specific immunosuppression by murine cardiac transplantation (2017)
  • Author(s): Hori, T., S. Uemoto, K. Saito, K. Kuribayashi, Y. Hori, and T. Kato.
  • Journal Title: Transplant Immunology Volume: 40 Pages: 72-73
  • DOI: 10.1016/j.trim.2016.12.005
  • Peer Reviewed
• [Journal Article] 腸内細菌とがん治療応答性 (2017)
  • Author(s): 加藤琢磨
  • Journal Title: 遺伝子医学MOOK Volume: 印刷中
• [Journal Article] Efficient Tumor Regression by Adoptively Transferred CEA-Specific CAR-T Cells Associated with Symptoms of Mild Cytokine Release Syndrome. (2016)
  • Author(s): Wang L, Ma N, Okamoto S, Amaishi Y, Sato E, Mineno J, Takesako K, Kato T and Shiku H.
  • Journal Title: OncoImmunology Volume: 5 Issue: 9 Pages: e1211218-e1211218
  • DOI: 10.1080/2162402x.2016.1211218
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Promising use of gene-modified γδ T cells for Cancer Immunotherapy (2018)
  • Author(s): Okumura S, Kato T, Wang Y, Hayashi T, Shirakura K, Ikeda H, Wang L, Miyahara Y, Tanaka Y, Shiku H.
  • Organizer: 日本癌学会
• [Presentation] Anti-tumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination (2018)
  • Author(s): Akahori Y, Wang L, Yoneyama M, Seo N, Okumura S, Miyahara Y, Amaishi Y, Okamoto S, Mineno J, Ikeda H, Maki T, Fujiwara H, Akatsuka Y, Kato T, Shiku H.
  • Organizer: 日本癌学会
• [Presentation] Anti-tumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination (2018)
  • Author(s): Akahori Y, Wang L, Yoneyama M, Seo N, Okumura S, Miyahara Y, Amaishi Y, Okamoto S, Mineno J, Ikeda H, Maki T, Fujiwara H, Akatsuka Y, Kato T, Shiku H.
  • Organizer: 日本がん免疫学会
• [Presentation] T cells expressing CAR harbouring GITR signalling domain exhibit prolonged in vivo survival and resistance to immunosuppression that lead to efficient tumor eradication (2017)
  • Author(s): Takuma Kato, Linan Wang, Sachiko Okamoto, Yasunori Amaishi, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, and Hiroshi Shiku
  • Organizer: 25th European Society for Gene and Cell Therapy
  • Int'l Joint Research
• [Presentation] Stromal cells modulated by IL-17A promote lung metastasis of breast cancer cells (2017)
  • Author(s): Kanako Saito, Takuma Kato, Naohiro Seo, Linan Wang, Toshimichi Yoshida, Hiroshi Shiku, Naoyuki Katayama
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Efficient tumor eradication by CAR-T with GITR signal due to prolonged persistency and resistance to immunosuppression (2017)
  • Author(s): Linan Wang, Takuma Kato, Sachiko Okamoto, Yasunori Amaishi, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, and Hiroshi Shiku
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] T cells expressing CAR harboring GITR signaling domain exhibit prolonged in vivo survival and resistance to immunosuppression that lead to efficient tumor eradication (2017)
  • Author(s): Takuma Kato, Linan Wang, Sachiko Okamoto, Yasunori Amaishi, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, and Hiroshi Shiku
  • Organizer: 日本遺伝子細胞治療学会
• [Presentation] Efficient tumor eradication by CAR-T with GITR signal due to prolonged persistency and resistance to immunosuppression (2017)
  • Author(s): Linan Wang, Takuma Kato, Sachiko Okamoto, Yasunori Amaishi, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, and Hiroshi Shiku
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] Efficient Tumour Regression by Adoptively Transferred CEA-Specific CAR-T Cells Associated with Symptoms of Mild Cytokine Release Syndrome which can be treated by anti-IL-6 receptor without compromising its efficacy (2016)
  • Author(s): Linan Wang, Ning Ma, Sachiko Okamoto, Yasunori Amaishi, Eiichi Sato, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, Takuma Kato and Hiroshi Shiku
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Efficient Tumour Regression by Adoptively Transferred CEA-Specific CAR-T Cells Associated with Symptoms of Mild Cytokine Release Syndrome which can be treated by anti-IL-6 receptor without compromising its efficacy (2016)
  • Author(s): Linan Wang, Ning Ma, Sachiko Okamoto, Yasunori Amaishi, Eiichi Sato, Naohiro Seo, Junichi Mineno, Kazutoh Takesako, Takuma Kato and Hiroshi Shiku
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 大阪国際交流センター（大阪府・大阪市）
  • Year and Date: 2016-07-27