Long-term clinical and molecular follow-up of large animals receiving retrovirally transduced stem and progenitor cells: no progression to clonal hematopoiesis or leukemia.
There has been significant progress toward clinically relevant levels of retroviral gene transfer into hematopoietic stem cells (HSC), and the therapeutic potential of HSC-based gene transfer has been convincingly demonstrated in children with severe combined immunodeficiency syndrome (SCID). However, the subsequent development of leukemia in two children with X-linked SCID who were apparently cured after transplantation of retrovirally corrected CD34+ cells has raised concerns regarding the safety of gene therapy approaches utilizing integrating vectors. Nonhuman primates and dogs represent the best available models for gene transfer safety and efficacy and are particularly valuable for evaluation of long-term effects. We have followed 42 rhesus macaques, 23 baboons, and 17 dogs with significant levels of gene transfer for a median of 3.5 years (range 1-7) after infusion of CD34+ cells transduced with retroviral vectors expressing marker or drug-resistance genes. None developed abnormal hematopoiesis or leukemia. Integration site analysis confirmed stable, polyclonal retrovirally marked hematopoiesis, without progression toward mono- or oligoclonality over time. These results suggest that retroviral integrations using replication-incompetent vectors, at copy numbers achieved using standard protocols, are unlikely to result in leukemogenesis and that patient- or transgene-specific factors most likely contributed to the occurrence of leukemia in the X-SCID gene therapy trial.
Clinical Research Division, Fred Hutchinson Cancer Research Center, and Division of Orcology, University of Washington, Seattle, WA, USA.
Hans-Peter
HP
Kiem
Stephanie
S
Sellers
Bobbie
B
Thomasson
Julia C
JC
Morris
John F
JF
Tisdale
Peter A
PA
Horn
Peiman
P
Hematti
Rima
R
Adler
Ken
K
Kuramoto
Boris
B
Calmels
Aylin
A
Bonifacino
Jiong
J
Hu
Christof
C
von Kalle
Manfred
M
Schmidt
Brian
B
Sorrentino
Arthur
A
Nienhuis
C Anthony
CA
Blau
Robert G
RG
Andrews
Robert E
RE
Donahue
Cynthia E
CE
Dunbar
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000473:pathology; D007938:Leukemia / Q000209:etiology / Q000473:pathology*; D008251:Macaca; D010215:Papio; D012190:Retroviridae / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors
D000906:Antibodies; D018952:Antigens, CD34