Inducible apoptosis as a safety switch for adoptive cell therapy

Antonio Di Stasi, Siok Keen Tey, Gianpietro Dotti, Yuriko Fujita, Alana Kennedy-Nasser, Caridad Martinez, Karin Straathof, Enli Liu, April G. Durett, Bambi Grilley, Hao Liu, Conrad R. Cruz, Barbara Savoldo, Adrian P. Gee, John Schindler, Robert A. Krance, Helen E. Heslop, David M. Spencer, Cliona M. Rooney, Malcolm K. Brenner

Research output: Contribution to journalArticle

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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.)

Original languageEnglish (US)
Pages (from-to)1673-1683
Number of pages11
JournalNew England Journal of Medicine
Volume365
Issue number18
DOIs
StatePublished - Nov 3 2011
Externally publishedYes

Fingerprint

Caspase 9
Graft vs Host Disease
Cell- and Tissue-Based Therapy
Apoptosis
T-Lymphocytes
Safety
Switch Genes
Pharmaceutical Preparations
Play Therapy
National Heart, Lung, and Blood Institute (U.S.)
Regenerative Medicine
National Cancer Institute (U.S.)
Dimerization
Stem Cell Transplantation
Transgenes
Suicide
Carrier Proteins
Leukemia
Cell Death
Stem Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Di Stasi, A., Tey, S. K., Dotti, G., Fujita, Y., Kennedy-Nasser, A., Martinez, C., ... Brenner, M. K. (2011). Inducible apoptosis as a safety switch for adoptive cell therapy. New England Journal of Medicine, 365(18), 1673-1683. https://doi.org/10.1056/NEJMoa1106152

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.; Brenner, Malcolm K.

In: New England Journal of Medicine, Vol. 365, No. 18, 03.11.2011, p. 1673-1683.

Research output: Contribution to journalArticle

Di Stasi, A, Tey, SK, Dotti, G, Fujita, Y, Kennedy-Nasser, A, Martinez, C, Straathof, K, Liu, E, Durett, AG, Grilley, B, Liu, H, Cruz, CR, Savoldo, B, Gee, AP, Schindler, J, Krance, RA, Heslop, HE, Spencer, DM, Rooney, CM & Brenner, MK 2011, 'Inducible apoptosis as a safety switch for adoptive cell therapy', New England Journal of Medicine, vol. 365, no. 18, pp. 1673-1683. https://doi.org/10.1056/NEJMoa1106152
Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C et al. Inducible apoptosis as a safety switch for adoptive cell therapy. New England Journal of Medicine. 2011 Nov 3;365(18):1673-1683. https://doi.org/10.1056/NEJMoa1106152
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. / Inducible apoptosis as a safety switch for adoptive cell therapy. In: New England Journal of Medicine. 2011 ; Vol. 365, No. 18. pp. 1673-1683.
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AU - Di Stasi, Antonio

AU - Tey, Siok Keen

AU - Dotti, Gianpietro

AU - Fujita, Yuriko

AU - Kennedy-Nasser, Alana

AU - Martinez, Caridad

AU - Straathof, Karin

AU - Liu, Enli

AU - Durett, April G.

AU - Grilley, Bambi

AU - Liu, Hao

AU - Cruz, Conrad R.

AU - Savoldo, Barbara

AU - Gee, Adrian P.

AU - Schindler, John

AU - Krance, Robert A.

AU - Heslop, Helen E.

AU - Spencer, David M.

AU - Rooney, Cliona M.

AU - Brenner, Malcolm K.

PY - 2011/11/3

Y1 - 2011/11/3

N2 - 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.)

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