Development of immunosuppressive microenvironment-breaking immune therapy with autologous hematopoietic stem cell transplantation

• Project/Area Number: 23590384
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: AOKI Kazunori 独立行政法人国立がん研究センター, 研究所, 分野長 (60270675)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫抑制環境 / 制御性Ｔ細胞 / 造血幹細胞移植 / 低酸素 / 遺伝子導入 / プロモーター / 免疫抑制性環境 / 腫瘍免疫

Research Abstract

We have reported that autologous hematopoietic stem cell transplantation (HSCT) leads to an induction of antitumor immunity. However, many solid cancers are resistant to immune therapies, because they establish the immunosuppressive microenvironment in tumors. The regulatory T cells (Tregs) is a main factor of tumoral immunosuppression. On the other hand, the systemic depletion of Tregs may induce autoimmune reaction. Here, we developed a novel immune therapy with the genetic engineering of hematopoietic stem cells, which fundamentally break the immunosuppressive microenvironment in tumors. To eradicate Tregs in tumors only, we first analyzed the dynamics of Tregs in tumors after HSCT, and based the findings, we successfully developed a hypoxia-inducible Treg-specific transgene expression system, which is a basis of novel immune therapy.

Research Products

• [Journal Article] Suppression of Tregs by anti-GITR antibody enhances the antitumor immunity of IFN-alpha gene therapy for pancreatic cancer. (2014)
  • Author(s): K. Aida, R. Miyakawa, K. Suzuki, K. Narumi, T. Udagawa, Y. Yamamoto, T. Chikaraishi, T. Yoshida, K. Aoki.
  • Journal Title: Cancer Science Volume: 105 Issue: 2 Pages: 636-645
  • DOI: 10.1111/cas.12332
  • Peer Reviewed
• [Journal Article] Pre-immunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation (2013)
  • Author(s): Suzuki K, Aida K, Miyakawa R, Narumi K, Udagawa T, Goto N, Yoshida T, Ohshima Y, Aoki K
  • Journal Title: Cancer Med Volume: 2 Pages: 636-645
• [Journal Article] VEGF-D-mediated blockade of regulatory T cells within tumors is induced by hematopoietic stem cell transplantation (2013)
  • Author(s): Udagawa T, Narumi K, Suzuki K, Aida K, Miyakawa R, Ikarashi Y, Makimoto A, Chikaraishi T, Yoshida T, Aoki K
  • Journal Title: J Immunol Volume: 191 Pages: 3440-3452
• [Journal Article] VEGF-D-mediated blockade of regulatory T cells within tumors is induced by hematopoietic stem cell transplantation. (2013)
  • Author(s): T. Udagawa, K. Narumi, K.Suzuki, K. Aida, R. Miyakawa, Y. Ikarashi, A. Makimoto, T. Chikaraishi, T. Yoshida and K. Aoki.
  • Journal Title: Journal of Immunology Volume: 191 Issue: 6 Pages: 3440-3452
  • DOI: 10.4049/jimmunol.1201454
  • Peer Reviewed
• [Journal Article] Pre-immunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation. (2013)
  • Author(s): K. Suzuki, K. Aida, R. Miyakawa, K. Narumi, T. Udagawa, N. Goto, T. Yoshida, Y. Ohshima, K. Aoki.
  • Journal Title: Cancer Medicine Volume: 2 Issue: 5 Pages: 636-645
  • DOI: 10.1002/cam4.117
  • Peer Reviewed
• [Journal Article] Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of intratumoral type I interferon gene transfer for sarcoma (2012)
  • Author(s): Udagawa T, Narumi K, Goto N, Aida K, Suzuki K, Makimoto A, Ochiya T, Yoshida T, Chikaraishi T, Aoki K
  • Journal Title: Hum. Gene Ther Volume: 23 Pages: 173-186
• [Journal Article] In vivo interferon-αgene transfer enhances antitumor immunity afterautologous hematopoietic stem cell transplantation (2012)
  • Author(s): Narumi K, Udagawa T, Kobayashi A, Hara H, Kondoh A, Goto N, Ikarashi Y, Ohnami S, Takeshita F, Ochiya T, Okada T, Yamagishi M, Yoshida T, Aoki K
  • Journal Title: Gene Ther Volume: 19 Pages: 34-48
• [Journal Article] Real-time zn vzvo cellular imaging of graft-versus-host disease and its reaction to immunomodulatory reagents, Immunology Letters (2012)
  • Author(s): Takahiro Yamazaki, Yoshinori Ikarashi et al.
  • Journal Title: Immunology Letters Volume: 144巻 Issue: 1-2 Pages: 33-40
  • DOI: 10.1016/j.imlet.2012.03.004
  • Peer Reviewed
• [Journal Article] Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of intratumoral type I interferon gene transfer for sarcoma (2012)
  • Author(s): Udagawa T, Narumi K, Goto N, Aida K, Suzuki K, Makimoto A, Ochiya T, Yoshida T, Chikaraishi T, Aoki K
  • Journal Title: Human Gene Therapy Volume: 23 Issue: 2 Pages: 173-186
  • DOI: 10.1089/hum.2011.046
  • Peer Reviewed
• [Journal Article] In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts (2011)
  • Author(s): Narumi, K., Udagawa, T., Kondoh, A., Kobayashi, A., Hara, H., Ikarashi, Y., Ohnami, S., Takeshita, F., Ochiya, T., Okada, T., Yamagishi, M., Yoshida, T., Aoki, K.
  • Journal Title: Gene Therapy Volume: 287 Issue: 1 Pages: 1397-1405
  • DOI: 10.1038/gt.2011.73
  • Peer Reviewed
• [Presentation] Antitumor immunity induced by autologous hematopoietic stem cell transplantation is enhanced by a priming of the donor T lymphocytes to tumor-associated antigens (2013)
  • Author(s): Narumi K, Suzuki K, Miyakawa R, Aida K, Yoshida T, Aoki K
  • Organizer: 9th AACR-Japanese Cancer Association Joint Conference
  • Place of Presentation: Maui
• [Presentation] A combination of IFN gene therapy and GITR ab-induced reduction of Tregs enhances antitumor immunity for pancreatic cancer. (2013)
  • Author(s): K. Aoki, K. Aida, K. Narumi, R. Miyakawa, N. Goto, H. Hashimoto, R. Ueda, Y. Ikarashi, S. Ohnami, T. Yoshida.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] S100A8/S100A9-mediated NK cell activation induces antitumor immunity after syngenetic hematopoietic stem cell transplantation. (2013)
  • Author(s): K. Narumi, R. Miyakawa, R. Ueda, H. Hashimoto, T. Yoshida, K. Aoki
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] VEGF-D-mediated suppression of regulatory T cells within tumors by hematopoietic stem cell transplantation (2012)
  • Author(s): Narumi K, T Udagawa T, Miyakawa R, Aoki K
  • Organizer: 第41回日本免疫学会総会
• [Presentation] 固形がんに対する新たな免疫遺伝子・細胞療法の開発 (2012)
  • Author(s): 青木一教
  • Organizer: 第6回日本緩和医療薬学会
• [Presentation] VEGF-D-mediated suppression of immune-tolerant microenvironment within tumors by hematopoietic stem cell transplantation (2012)
  • Author(s): Miyakawa R, Suzuki K, Aida K, Goto N, Narumi K, Yoshida T, Aoki K
  • Organizer: 第71回日本癌学会総会
• [Presentation] Antitumor immunity of hematopoietic stem cell transplantation differs by a priming status of donor cells (2012)
  • Author(s): Suzuki K, Miyakawa R, Aida K, Goto N, Narumi K, Yoshida T, Aoki K
  • Organizer: 第71回日本癌学会総会
• [Presentation] Suppression of immune-tolerant microenvironment within tumors by hematopoietic stem cell transplantation (2012)
  • Author(s): Aoki K, Udagawa T, Narumi K
  • Organizer: 第71回日本癌学会総会
• [Presentation] Combination therapy of hematopoietic stem cell transplantation and intratumoral interferon gene transfer to sarcoma (Symposium) (2012)
  • Author(s): Aoki K, Narumi K, Udagawa T
  • Organizer: 第18回日本遺伝子治療学会学術集会
• [Presentation] Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of intratumoral type I interferon gene transfer for sarcoma (2012)
  • Author(s): Narumi K, Udagawa T, Aida K, Suzuki K, Makimoto A, Aoki K
  • Organizer: The American Society of Gene Therapy's 15th Annual Meeting
  • Place of Presentation: Philadelphia
• [Presentation] Combination therapy of hematopoietic stem cell transplantation and intratumoral interferon gene transfer to sarcoma (2012)
  • Author(s): K Aoki, K Narumi, T Udagawa.
  • Organizer: 第18回日本遺伝子治療学会学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] Suppression of immune-tolerant microenvironment within tumors by hematopoietic stem cell transplantation (2012)
  • Author(s): K Aoki, T Udagawa, K Narumi.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] Antitumor immunity of hematopoietic stem cell transplantation differs by a priming status of donor cells (2012)
  • Author(s): K Suzuki, R Miyakawa, K Aida, N Goto, K Narumi, T Yoshida, K Aoki
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] VEGF-D-mediated suppression of immune-tolerant microenvironment within tumors by hematopoietic stem cell transplantation (2012)
  • Author(s): R Miyakawa1, K Suzuki, K Aida, N Goto, K Narumi, T Yoshida, K Aoki
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] In vivo delivery of interferon-αgene enhances tumor immunity and suppresses immunotolerance after autologous hematopoietic stem cell transplantation (2011)
  • Author(s): K Narumi, T Udagawa, Y Ikarashi, T Ochiya, T Yoshida, K Aoki
  • Organizer: The American Society of Gene Therapy's 14th Annual Meeting
  • Place of Presentation: Seattle
• [Presentation] Autologous hematopoietic stem cell transplantation suppresses immunotolerant environment in tumors and induces antitumor immunity (2011)
  • Author(s): T Udagawa, K Narumi, Y Ikarashi, S Ohnami, T Yoshida, K Aoki
  • Organizer: 第70回日本癌学会総会
• [Presentation] Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of type I interferon gene transfer for sarcoma (2011)
  • Author(s): T Udagawa, K Narumi, T Ochiya, T Yoshida, K Aoki
  • Organizer: 第17回日本遺伝子治療学会学術集会
• [Presentation] In vivo delivery of interferon-alpha gene enhances tumor immunity and suppresses immunotolerance after autologous hematopoietic stem cell transplantation. (2011)
  • Author(s): Narumi K, Udagawa T, Ikarashi Y, Ochiya T, Yoshida T, Aoki K
  • Organizer: The American Society of Gene Therapy’s 14th Annual Meeting
  • Place of Presentation: Seattle, USA
• [Presentation] Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of type I interferon gene transfer for sarcoma. (2011)
  • Author(s): Udagawa T, Narumi K, Ochiya T, Yoshida T, Aoki K
  • Organizer: 第17回日本遺伝子治療学会学術集会
  • Place of Presentation: 博多
• [Presentation] Autologous hematopoietic stem cell transplantation suppresses immunotolerant environment in tumors and induces antitumor immunity. (2011)
  • Author(s): Udagawa T, Narumi K, Ikarashi Y, Ohnami S, Yoshida T, Aoki K
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
• [Book] Combination of immune gene therapy with allogeneic hematopoietic stem cell transplantation against solid cancers. In : Cellular and Genetic Practices for Translational Medicine ed. by J-Y. Kwak and J-Y (2011)
  • Author(s): Narumi K, Aoki K
  • Publisher: Han. Research Signpost, Kerala, India
• [Book] Cellular and Genetic Practices for Translational Medicine (2011)
  • Author(s): Narumi K, Aoki K.
  • Total Pages: 260
  • Publisher: Research Signpost