Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation

Tey, Siok-Keen, Dotti, Gianpietro, Rooney, Cliona M., Heslop, Helen E. and Brenner, Malcolm K. (2007) Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biology of Blood and Marrow Transplantation, 13 8: 913-924. doi:10.1016/j.bbmt.2007.04.005


Author Tey, Siok-Keen
Dotti, Gianpietro
Rooney, Cliona M.
Heslop, Helen E.
Brenner, Malcolm K.
Title Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation
Journal name Biology of Blood and Marrow Transplantation   Check publisher's open access policy
ISSN 1083-8791
1523-6536
Publication date 2007-08
Sub-type Article (original research)
DOI 10.1016/j.bbmt.2007.04.005
Volume 13
Issue 8
Start page 913
End page 924
Total pages 12
Place of publication United States
Publisher Carden Jennings Publishing
Language eng
Subject 11 Medical and Health Sciences
1103 Clinical Sciences
Abstract Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19). Even after allodepletion (using anti-CD25 immunotoxin), donor T cells could be efficiently transduced, expanded, and subsequently enriched by CD19 immunomagnetic selection to >90% purity. These engineered cells retained antiviral specificity and functionality, and contained a subset with regulatory phenotype and function. Activating iCasp9 with a small-molecule dimerizer rapidly produced >90% apoptosis. Although transgene expression was downregulated in quiescent T cells, iCasp9 remained an efficient suicide gene, as expression was rapidly upregulated in activated (alloreactive) T cells. We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials.
Keyword Hematopoietic stem cell transplantation
Graft-versus-host disease
Gene therapy
T lymphocyte
Immunotherapy
Haploidentical
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Mon, 11 Jan 2010, 08:50:20 EST by Ms May Balasaize on behalf of Faculty Of Health Sciences