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Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma

Beane, Joal D et al.

Molecular therapy. Volume 23:Number 8 (2015, August); pp 1380-1390 -- Cell Press

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  • Title:
    Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma
  • Author: Beane, Joal D;
    Lee, Gary;
    Zheng, Zhili;
    Mendel, Matthew;
    Abate-Daga, Daniel;
    Bharathan, Mini;
    Black, Mary;
    Gandhi, Nimisha;
    Yu, Zhiya;
    Chandran, Smita;
    Giedlin, Martin;
    Ando, Dale;
    Miller, Jeff;
    Paschon, David;
    Guschin, Dmitry;
    Rebar, Edward J;
    Reik, Andreas;
    Holmes, Michael C;
    Gregory, Philip D;
    Restifo, Nicholas P;
    Rosenberg, Steven A;
    Morgan, Richard A;
    Feldman, Steven A
  • Found In: Molecular therapy. Volume 23:Number 8 (2015, August); pp 1380-1390
  • Journal Title: Molecular therapy
  • Subjects: Gene therapy--Periodicals; Molecular genetics--Periodicals; Dewey: 615.89505
  • Rights: Licensed
  • Publication Details: Cell Press
  • Abstract: Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% ( n = 3, range 69.9–84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500–2, 000-fold in vitro . Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.
  • Identifier: System Number: ETOCvdc_100062566342.0x000001; Journal ISSN: 1525-0016; doi/10.1038/mt.2015.71
  • Publication Date: 2015
  • Physical Description: Electronic
  • Shelfmark(s): 5900.856500
  • UIN: ETOCvdc_100062566342.0x000001

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