Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer

 E. Provasi, et al. Nat Med. 2012 18(5):807-15

Speaker: Jia-Ying Hung (洪家瑩)                         Time: 15:00~16:00, May. 29, 2013

Commentator: Dr. Ai-Li Shiau (蕭璦莉 博士)  Place: Room 601

Abstract：

Transferring high avidity T cell receptors (TCRs) recognizing tumor antigen into polyclonal T cells is a new approach for cancer therapy. But there are limitations in current gene transferring technologies, such as lack of stable high level expression and mispair with endogenous TCRs resulting in unpredictable reactivity. Therefore, the authors designed Zn finger nucleases (ZFNs) as a strategy to disrupt endogenous TCR production of T cells. ZFNs can edit T cell specificity at DNA level (1). It is composed of a tandem array of C₂H₂ Zn finger binding domains which can be designed to specifically bind target DNA sequence, coupled to the catalytic domain from the type IIS restriction enzyme fokI resulting in double strand break (DSB) at target genomic site. DSBs are then repaired by non-homologous end joining (NHEJ) which often causes nucleotide deletions or insertions at the site of the break, and thus disrupts of the target gene. After transferred a TCR specific for Wilms tumor 1 (WT1) antigen by lentiviral vector, edited T cells express WT1 specific TCR at high levels. Since the disruption of endogenous TCRs prevents unwanted misparing, it mayreduced unpredictable alloreactivity of clonal TCR transferred T cells. Mice received unedited T cells expressing WT1 specific TCR died for graft versus host disease (GVHD) within two weeks, while none of the mice received edited T cells expressing WT1 specific TCR died in observation period up to four weeks after treatment. In summary, T cell editing improves biosafety of clonal TCR expressing T cells that provides a great potential of application in cancer therapy.

References：

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