Inducible apoptosis as a safety switch for adoptive cell therapy

Di Stasi, Antonio, Tey, Siok-Keen, Dotti, Gianpietro, Fujita, Yuriko, Kennedy-Nasser, Alana, Martinez, Caridad, Straathof, Karin, Liu, Enli, Durett, April G., Grilley, Bambi, Liu, Hao, Cruz, Conrad R., Savoldo, Barbara, Gee, Adrian P., Schindler, John, Krance, Robert A., Heslop, Helen E., Spencer, David M., Rooney, Cliona M. and Brenner, Malcolm K. (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. New England Journal of Medicine, 365 18: 1673-1683. doi:10.1056/NEJMoa1106152

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Author Di Stasi, Antonio
Tey, Siok-Keen
Dotti, Gianpietro
Fujita, Yuriko
Kennedy-Nasser, Alana
Martinez, Caridad
Straathof, Karin
Liu, Enli
Durett, April G.
Grilley, Bambi
Liu, Hao
Cruz, Conrad R.
Savoldo, Barbara
Gee, Adrian P.
Schindler, John
Krance, Robert A.
Heslop, Helen E.
Spencer, David M.
Rooney, Cliona M.
Brenner, Malcolm K.
Title Inducible apoptosis as a safety switch for adoptive cell therapy
Journal name New England Journal of Medicine   Check publisher's open access policy
ISSN 0028-4793
1533-4406
Publication date 2011-11-01
Sub-type Article (original research)
DOI 10.1056/NEJMoa1106152
Open Access Status File (Publisher version)
Volume 365
Issue 18
Start page 1673
End page 1683
Total pages 11
Place of publication Boston, MA, United States
Publisher Massachusetts Medical Society
Language eng
Formatted 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.)
Keyword Cytotoxic T-lymphocytes
Graft-versus-leukemia
Immunotherapy
Transplantation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Medicine Publications
 
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Created: Tue, 13 Dec 2011, 23:13:19 EST by Matthew Lamb on behalf of School of Medicine