Development of switch promoters driven by activation signals from the chimeric antigen receptors.

• Project/Area Number: 24700995
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor immunology
• Research Institution: Jichi Medical University
• Principal Investigator: UCHIBORI Ryosuke 自治医科大学, 医学部, 助教 (20458285)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: キメラ抗原受容体 / 細胞・遺伝子治療 / がん / シグナル伝達 / 分子スイッチ

Research Abstract

Chimeric antigen receptor (CAR)-based immunotherapy shows therapeutic efficacy. However additional genetic modification is necessary for enhancement of the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor sites. In this study, we aimed at developing switch promoters that would respond to activation signals from a CAR. We prepared a switch cassette that was arranged in order of two SV40 polyAs, four NFAT-REs, a minimal IL-2 promoter, ZsGreen1, and a BGH polyA sequence. Genes encoding switch cassettes were transferred into CD19-targeted CAR-expressing PBMCs. ZsGreen1 expression in PBMCs was strongly induced by co-culture with CD19-positive target cells.

Research Products

• [Journal Article] CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models (2013)
  • Author(s): Tsukahara T, Ohmine K, Yamamoto C, Uchibori R, Ido H, Teruya T, Urabe M, Mizukami H, Kume A, Nakamura M, Mineno J, Takesako K, Riviere I, Sadelain M, Brentjens R, Ozawa K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 438 Issue: 1 Pages: 84-89
  • DOI: 10.1016/j.bbrc.2013.07.030
  • Peer Reviewed
• [Journal Article] NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites. (2013)
  • Author(s): Uchibori R, Tsukahara T, Mizuguchi H, Saga Y, Urabe M, Mizukami H, Kume A, Ozawa K
  • Journal Title: Cancer Research Volume: 73 Issue: 1 Pages: 364-372
  • DOI: 10.1158/0008-5472.can-12-0088
  • Peer Reviewed
• [Presentation] Development of switch promoters driven by activation signals from the chimeric antigen receptors (2013)
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ohmine K, Urabe M, Mizukami H, Kume A, Mineno J, Ozawa K
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] Development of switch promoters that would respond to activation signals from the chimeric antigen receptors (2013)
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] DEVELOPMENT OF SIN RETROVIRAL VECTORS EQUIPPED WITH SWITCH PROMOTERS DRIVEN BY ACTIVATION SIGNALS FROM THE CHIMERIC ANTIGEN RECEPTORS (2013)
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K
  • Organizer: 第18回日本遺伝子治療学会
  • Place of Presentation: 岡山
  • Year and Date: 2013-07-06
• [Presentation] DEVELOPMENT OF SIN RETROVIRAL VECTORS EQUIPPED WITH SWITCH PROMOTERS DRIVEN BY ACTIVATION SIGNALS FROM THE CHIMERIC ANTIGEN RECEPTORS.
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
  • Organizer: 第18回日本遺伝子治療学会
  • Place of Presentation: 岡山
• [Presentation] Development of switch promoters that would respond to activation signals from the chimeric antigen receptors.
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Development of switch promoters driven by activation signals from the chimeric antigen receptors.
  • Author(s): Uchibori R, Ninomiya S, Tsukahara T, Ohmine K, Urabe M, Mizukami H, Kume A, Mineno J, Ozawa K.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌