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Long-term outcome and immune reconstitution after haploidentical stem cell transplant in recipients of allodepleted-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 and Gianpietro Dotti

Key points

  • Allodepleted-T-cells containing the iC9 safety gene persist long term in vivo, promote immune recovery and protect against infections.

  • GvHD caused by iC9-T cells can be permanently controlled by a single administration of AP1903 without abrogating immune reconstitution.

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 of 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 term follow-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 naïve 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 is registered at www.clinicaltrials.gov as NCT00710892.

  • Submitted January 28, 2014.
  • Accepted April 14, 2014.