Development of redirected T cell-based adoptive immunotherapy targeting leukemia stem cells

• Project/Area Number: 26830109
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Ehime University
• Principal Investigator: ASAI HIROAKI 愛媛大学, 医学部附属病院, 講師(病院職員) (00726838)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 細胞免疫療法 / 白血病性幹細胞 / WT1

Outline of Final Research Achievements

Suppression of leukemia stem cells (LSC) is reasonably necessary to cure the leukemia. To this end, we are developing a redirected T cell-based adoptive immunotherapy targeting WT1, which LSCs have been shown to overexpress. In this study, we have demonstrated WT1-siTCR/CD8+ T cells killed Fucci-labeled leukemia cell lines irrelevantly to the cell-cycle status of target leukemia cells with in vitro time lapse assay, and also demonstrated WT1-siTCR/CD8+ T cells seem be able to kill cell-cycle quiescent LSCs using a xenograft NOG mouse model in vivo. In addition, we found that WT1-siTCR/CD4+ T cells migrated to leukemia sites, subsequently attracted WT1-siTCR/CD8+ T cells via chemotaxis, and augmented cytocidal activity against human leukemia through longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8+ T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia.

Research Products

• [Journal Article] Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer. (2015)
  • Author(s): Fujiwara H, Ochi T, Ochi F, Miyazaki Y, Asai H, Narita M, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M.
  • Journal Title: Leukemia Volume: 29(12) Issue: 12 Pages: 2393-2401
  • DOI: 10.1038/leu.2015.155
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] TCR遺伝子改変HLAクラスI拘束性CD4陽性T細胞サブタイプ作成の試み (2014)
  • Author(s): 朝井洋晶、藤原弘、安川正貴ほか
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27