Inducible apoptosis as a safety switch for adoptive cell therapy.
N Engl J Med
; 365(18): 1673-83, 2011 Nov 03.
Article
em En
| MEDLINE
| ID: mdl-22047558
ABSTRACT
BACKGROUND:
Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.METHODS:
We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.RESULTS:
Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.CONCLUSIONS:
The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Imunoterapia Adotiva
/
Proteínas de Ligação a Tacrolimo
/
Genes Transgênicos Suicidas
/
Caspase 9
/
Doença Enxerto-Hospedeiro
Limite:
Adolescent
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
N Engl J Med
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos