Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft.

Abstract : 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.
Type de document :
Article dans une revue
Blood, American Society of Hematology, 2007, 110 (12), pp.3842-52. 〈10.1182/blood-2007-04-087346〉
Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-00479711
Contributeur : Philippe Saas <>
Soumis le : dimanche 2 mai 2010 - 12:39:44
Dernière modification le : lundi 9 juillet 2018 - 13:12:02

Lien texte intégral

Identifiants

Collections

Citation

Marina Deschamps, Patricia Mercier-Lethondal, Jean-Marie Certoux, Carole Henry, Bruno Lioure, et al.. Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft.. Blood, American Society of Hematology, 2007, 110 (12), pp.3842-52. 〈10.1182/blood-2007-04-087346〉. 〈inserm-00479711〉

Partager

Métriques

Consultations de la notice

166