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

被引:93
作者
Beane, Joal D. [1 ,2 ]
Lee, Gary [3 ]
Zheng, Zhili [1 ]
Mendel, Matthew [3 ]
Abate-Daga, Daniel [1 ]
Bharathan, Mini [1 ]
Black, Mary [1 ]
Gandhi, Nimisha [3 ]
Yu, Zhiya [1 ]
Chandran, Smita [1 ]
Giedlin, Martin [3 ]
Ando, Dale [3 ]
Miller, Jeff [3 ]
Paschon, David [3 ]
Guschin, Dmitry [3 ]
Rebar, Edward J. [3 ]
Reik, Andreas [3 ]
Holmes, Michael C. [3 ]
Gregory, Philip D. [3 ]
Restifo, Nicholas P. [1 ]
Rosenberg, Steven A. [1 ]
Morgan, Richard A. [1 ]
Feldman, Steven A. [1 ]
机构
[1] NCI, Surg Branch, Bethesda, MD 20892 USA
[2] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA
[3] Sangamo BioSci, Richmond, CA USA
基金
美国国家卫生研究院;
关键词
CD8; T-CELLS; CANCER REGRESSION; PROGRAMMED DEATH-1; ANTI-PD-1; ANTIBODY; B7; FAMILY; IMMUNOTHERAPY; RECEPTOR; EXPRESSION; INFECTION; BLOCKADE;
D O I
10.1038/mt.2015.71
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 (TNF alpha, GM-CSF, and IFN gamma) 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.
引用
收藏
页码:1380 / 1390
页数:11
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