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Blood, 1 October 2009, Vol. 114, No. 14, pp. 2888-2899. Prepublished online as a Blood First Edition Paper on July 9, 2009; DOI 10.1182/blood-2009-01-199216. This Article Full Text (PDF) All Versions of this Article: blood-2009-01-199216v1 114/14/2888    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Burns, W. R. Articles by Morgan, R. A. PubMed PubMed Citation Articles by Burns, W. R. Articles by Morgan, R. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 12, 2009 Accepted June 21, 2009 Lack of specific -retroviral vector LTR promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation William R. Burns, Zhili Zheng, Steven A. Rosenberg, and Richard A. Morgan* Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States * Corresponding author; email: rmorgan{at}mail.nih.gov. Retroviral transduction of tumor antigen-specific T-cell receptor (TCR) genes into lymphocytes redirects T-cells to lyse tumors. Furthermore, adoptive transfer of these lymphocytes has mediated objective responses in patients with metastatic cancer. From 2004-2006, over 40 patients were treated with autologous gene-modified lymphocytes expressing a melanoma antigen-specific TCR at the National Cancer Institute. Eighteen such patients were analyzed for persistence and gene expression in vivo. Additionally, the impact of epigenetic silencing and of lymphocyte restimulation was studied. Although gene-modified lymphocytes persisted in vivo, shutdown of TCR transgene expression was observed. Bisulfite sequencing analysis and ex vivo DNA methyltransferase inhibition demonstrated that the decrease in gene expression did not result from DNA methylation. Surprisingly, downregulation of vector-driven transgene transcriptional activity was not vector-specific, but mimicked that of endogenous genes. The decline in TCR transgene expression, however, was reversed upon lymphocyte stimulation. These data demonstrate a lack of -retroviral promoter-specific gene silencing in adoptively transferred human lymphocytes and support that transgene expression is largely affected by global cellular mechanisms. The use of immunomodulatory adjuvants, e.g. vaccination or cytokine therapy, for in vivo T-cell activation may help overcome this metabolic quiescence and thus augment cellular immunotherapy-based cancer therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The hidden (and lazy) TCR Chiara Bonini and Vincenzo Russo Blood 2009 114: 2855-2856. [Full Text] [PDF] This article has been cited by other articles: C. Bonini and V. Russo The hidden (and lazy) TCR Blood, October 1, 2009; 114(14): 2855 - 2856. [Full Text] [PDF]

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