Title |
Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma
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Published in |
Molecular Therapy, May 2015
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DOI | 10.1038/mt.2015.71 |
Pubmed ID | |
Authors |
Joal D Beane, Gary Lee, Zhili Zheng, Matthew Mendel, Daniel Abate-Daga, Mini Bharathan, Mary Black, Nimisha Gandhi, Zhiya Yu, Smita Chandran, Martin Giedlin, Dale Ando, Jeff Miller, David Paschon, Dmitry Guschin, Edward J Rebar, Andreas Reik, Michael C Holmes, Philip D Gregory, Nicholas P Restifo, Steven A Rosenberg, Richard A Morgan, Steven A Feldman |
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 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 - 2000 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.Molecular Therapy (2015); doi:10.1038/mt.2015.71. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 5 | 45% |
Comoros | 1 | 9% |
Russia | 1 | 9% |
Unknown | 4 | 36% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 10 | 91% |
Scientists | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 1% |
Unknown | 138 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 31 | 22% |
Researcher | 30 | 21% |
Student > Master | 14 | 10% |
Student > Bachelor | 11 | 8% |
Student > Doctoral Student | 8 | 6% |
Other | 16 | 11% |
Unknown | 30 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 31 | 22% |
Biochemistry, Genetics and Molecular Biology | 23 | 16% |
Immunology and Microbiology | 19 | 14% |
Medicine and Dentistry | 17 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 4% |
Other | 15 | 11% |
Unknown | 29 | 21% |