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

作者：Xiaoou Zhou, Antonio Di Stasi, Siok‐Keen Tey, Robert A. Krance, Caridad A. Martinez, Kathryn S. Leung, April G. Durett, Meng-Fen Wu, Hao Liu, Ann Marie Leen, Barbara Savoldo, Yu‐Feng Lin, Bambi Grilley, Adrian P. Gee, David M. Spencer, Cliona M. Rooney, Helen Elisabeth Heslop, Malcolm K. Brenner, Gianpietro Dotti · 发表于：Blood · 年份：2014 · DOI：10.1182/blood-2014-01-551671 · 被引用次数：171 · 研究领域：Hematopoietic Stem Cell Transplantation、CAR-T cell therapy research、Virus-based gene therapy research

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-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 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.