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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3842-3852. Prepublished online as a Blood First Edition Paper on August 23, 2007; DOI 10.1182/blood-2007-04-087346. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-04-087346v1 110/12/3842    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Deschamps, M. Articles by Ferrand, C. Search for Related Content PubMed PubMed Citation Articles by Deschamps, M. Articles by Ferrand, C. Related Collections Transplantation Gene Therapy Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft Marina Deschamps1,4, Patricia Mercier-Lethondal1,3, Jean Marie Certoux1,3, Carole Henry1,3, Bruno Lioure5, Céline Pagneux4, Jean Yves Cahn6, Eric Deconinck1,2,7, Eric Robinet1,3, Pierre Tiberghien1,3, and Christophe Ferrand1,3 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U645, Besançon; 2 Université de Franche-Comte, Institut Fédératif de Recherche (IFR) 133, Besançon; 3 Etablissement Français du Sang Bourgogne Franche-Comté (EFS-BFC), Immuno-Molecular Therapeutics Laboratory, Besançon; 4 EFS-BFC, Clinical Biomonitoring Laboratory, Besançon; 5 Centre Hospitalier Universitaire (CHU) Strasbourg, Hematology Department, Strasbourg; 6 University Hospital Grenoble, Université Joseph Fourier, INSERM U823, Grenoble; and 7 CHU Besançon, Hematology Department, Besançon, France In our previous phase 1/2 study aimed at controlling graft-versus-host disease, 12 patients received Herpes simplex virus thymidine kinase (HSV-tk+)/neomycin phosphotransferase (NeoR+)–expressing donor gene-modified T cells (GMCs) and underwent an HLA-identical sibling T-cell–depleted bone marrow transplantation (BMT). This study's objective was to follow up, to quantify, and to characterize persistently circulating GMCs more than 10 years after BMT. Circulating GMCs remain detectable in all 4 evaluable patients. However, NeoR- and HSV-tk–polymerase chain reaction (PCR) differently quantified in vivo counts, suggesting deletions within the HSV-tk gene. Further experiments, including a novel "transgene walking" PCR method, confirmed the presence of deletions. The deletions were unique, patient-specific, present in most circulating GMCs expressing NeoR, and shown to occur at time of GMC production. Unique patient-specific retroviral insertion sites (ISs) were found in all GMCs capable of in vitro expansion/cloning as well. These findings suggest a rare initial gene deletion event and an in vivo survival advantage of rare GMC clones resulting from an anti–HSV-tk immune response and/or ganciclovir treatment. In conclusion, we show that donor mature T cells infused with a T-cell–depleted graft persist in vivo for more than a decade. These cells, containing transgene deletions and subjected to significant in vivo selection, represent a small fraction of T cells infused at transplantation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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