Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients

Détails

ID Serval
serval:BIB_A984D9BE9F25
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients
Périodique
Blood
Auteur⸱e⸱s
Cooper A. R., Lill G. R., Shaw K., Carbonaro-Sarracino D. A., Davila A., Sokolic R., Candotti F., Pellegrini M., Kohn D. B.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Statut éditorial
Publié
Date de publication
2017
Volume
129
Numéro
19
Pages
2624-2635
Langue
anglais
Notes
Cooper, Aaron R
Lill, Georgia R
Shaw, Kit
Carbonaro-Sarracino, Denise A
Davila, Alejandra
Sokolic, Robert
Candotti, Fabio
Pellegrini, Matteo
Kohn, Donald B
eng
M01 RR000043/RR/NCRR NIH HHS/
M01 RR000865/RR/NCRR NIH HHS/
R01 FD003005/FD/FDA HHS/
T32 GM007185/GM/NIGMS NIH HHS/
Clinical Trial
Blood. 2017 May 11;129(19):2624-2635. doi: 10.1182/blood-2016-12-756734. Epub 2017 Mar 28.
Résumé
Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near MECOM and LMO2 These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulted from expansion of a transduced natural killer clone in response to chronic Epstein-Barr virus viremia. Clonal diversity and T-cell repertoire, measured by vector integration site sequencing and T-cell receptor beta-chain rearrangement sequencing, correlated significantly with the amount of busulfan preconditioning delivered to patients and to CD34+ cell dose. These data, in combination with results of other ADA-SCID gene therapy trials, suggest that disease background may be a crucial factor in leukemogenic potential of retroviral gene therapy and underscore the importance of cytoreductive conditioning in this type of gene therapy approach.
Mots-clé
Adaptor Proteins, Signal Transducing/genetics, Adenosine Deaminase/*deficiency/genetics, Agammaglobulinemia/*genetics/pathology/*therapy, Antineoplastic Agents, Alkylating/*therapeutic use, Busulfan/*therapeutic use, Child, DNA-Binding Proteins/genetics, Gammaretrovirus/*genetics, Genetic Therapy/*methods, Genetic Vectors/genetics/*therapeutic use, Humans, LIM Domain Proteins/genetics, Proto-Oncogene Proteins/genetics, Proto-Oncogenes/genetics, Severe Combined Immunodeficiency/*genetics/pathology/*therapy, T-Lymphocytes/cytology/drug effects/metabolism/pathology, Transcription Factors/genetics
Pubmed
Open Access
Oui
Création de la notice
01/11/2017 11:29
Dernière modification de la notice
20/08/2019 16:13
Données d'usage