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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5168-5177.
Prepublished online as a Blood First Edition Paper on March 12, 2007; DOI 10.1182/blood-2006-06-029173.
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Submitted June 15, 2006
Accepted February 24, 2007
Cytokine independent growth and clonal expansion of a primary human CD8+ T cell clone following retroviral transduction with the IL-15 gene
Cary Hsu, Stephanie A Jones, Cyrille J Cohen, Zhili Zheng, Keith Kerstann, Juhua Zhou, Paul F Robbins, Peter D Peng, Xinglei Shen, Theotonius J Gomes, Cynthia E Dunbar, David J Munroe, Claudia Stewart, Kenneth Cornetta, Danny Wangsa, Thomas Ried, Steven A Rosenberg, and Richard A Morgan*
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Laboratory of Molecular Technology, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
* Corresponding author; email: morgan{at}mail.nih.gov.
Malignancies arising from retrovirally transduced hematopoietic stem cells have been reported in animal models and human gene therapy trials. Whether mature lymphocytes are susceptible to insertional mutagenesis is unknown. We have characterized a primary human CD8+ T cell clone which exhibited logarithmic ex-vivo growth in the absence of exogenous cytokine support for greater than 1 year after transduction with a MLV-based vector encoding the T cell growth factor IL-15. Phenotypically, the clone was CD28-, CD45RA-, CD45RO+, and CD62L-, a profile consistent with effector memory T lymphocytes. After gene transfer with tumor antigen-specific T cell receptors, the clone secreted IFN- upon encountering tumor targets, providing further evidence that they derived from mature lymphocytes. Gene expression analyses revealed no evidence of insertional activation of genes flanking the retroviral insertion sites. The clone exhibited constitutive telomerase activity, and the presence of autocrine loop was suggested by impaired cell proliferation following knockdown of the IL-15R . The generation of this cell line suggests that non-physiological expression of IL-15 can result in the long-term in vitro growth of mature human T lymphocytes. The cytokine-independent growth of this line was a rare event that has not been observed in other IL-15 vector transductions experiments or with any other integrating vector system. It does not appear that the retroviral vector integration sites played a role in the continuous growth of this cell clone, but this remains under investigation.
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