Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

Xiaoou Zhou, Antonio Di Stasi, Siok Keen Tey, Robert A. Krance, Caridad Martinez, Kathryn S. Leung, April G. Durett, Meng Fen Wu, Hao Liu, Ann M. Leen, Barbara Savoldo, Yu Feng Lin, Bambi J. Grilley, Adrian P. Gee, David M. Spencer, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner, Gianpietro Dotti

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small-molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-termfollow-up of 10 patients infused with such safety switch-modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892.

Original languageEnglish (US)
Pages (from-to)3895-3905
Number of pages11
JournalBlood
Volume123
Issue number25
DOIs
StatePublished - Jun 19 2014
Externally publishedYes

Fingerprint

Transplants
T-cells
Caspase 9
Stem cells
Transgenes
Stem Cells
T-Lymphocytes
Safety
Graft vs Host Disease
Grafts
Hematopoietic Stem Cells
Viruses
Switches
Tissue Donors
BK Virus
Adoptive Transfer
Pathogens
Cytomegalovirus
Human Herpesvirus 4
Adenoviridae

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Zhou, X., Di Stasi, A., Tey, S. K., Krance, R. A., Martinez, C., Leung, K. S., ... Dotti, G. (2014). Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood, 123(25), 3895-3905. https://doi.org/10.1182/blood-2014-01-551671

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. / Zhou, Xiaoou; Di Stasi, Antonio; Tey, Siok Keen; Krance, Robert A.; Martinez, Caridad; Leung, Kathryn S.; Durett, April G.; Wu, Meng Fen; Liu, Hao; Leen, Ann M.; Savoldo, Barbara; Lin, Yu Feng; Grilley, Bambi J.; Gee, Adrian P.; Spencer, David M.; Rooney, Cliona M.; Heslop, Helen E.; Brenner, Malcolm K.; Dotti, Gianpietro.

In: Blood, Vol. 123, No. 25, 19.06.2014, p. 3895-3905.

Research output: Contribution to journalArticle

Zhou, X, Di Stasi, A, Tey, SK, Krance, RA, Martinez, C, Leung, KS, Durett, AG, Wu, MF, Liu, H, Leen, AM, Savoldo, B, Lin, YF, Grilley, BJ, Gee, AP, Spencer, DM, Rooney, CM, Heslop, HE, Brenner, MK & Dotti, G 2014, 'Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene', Blood, vol. 123, no. 25, pp. 3895-3905. https://doi.org/10.1182/blood-2014-01-551671
Zhou, Xiaoou ; Di Stasi, Antonio ; Tey, Siok Keen ; Krance, Robert A. ; Martinez, Caridad ; Leung, Kathryn S. ; Durett, April G. ; Wu, Meng Fen ; Liu, Hao ; Leen, Ann M. ; Savoldo, Barbara ; Lin, Yu Feng ; Grilley, Bambi J. ; Gee, Adrian P. ; Spencer, David M. ; Rooney, Cliona M. ; Heslop, Helen E. ; Brenner, Malcolm K. ; Dotti, Gianpietro. / Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. In: Blood. 2014 ; Vol. 123, No. 25. pp. 3895-3905.
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AU - Martinez, Caridad

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