title: Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene.
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-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.
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stasi
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Caridad
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Leung
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: April G
authors.initials: AG
authors.lastname: Durett
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and Biostatistics Shared Resource, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX;
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.affiliation: Biostatistics Shared Resource, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX;
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Bambi J
authors.initials: BJ
authors.lastname: Grilley
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.affiliation: Bellicum Pharmaceuticals Inc., Houston, TX; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and Houston Methodist Hospital, Houston, TX.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.affiliation: Texas Children's Hospital, Houston, TX; Center for Cell and Gene Therapy and Houston Methodist Hospital, Houston, TX.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.affiliation: Center for Cell and Gene Therapy and.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
mesh_terms: D000293:Adolescent; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D001232:Aspergillus fumigatus / Q000276:immunology; D053453:Caspase 9 / Q000096:biosynthesis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D017728:Lymphoma, Large-Cell, Anaplastic / Q000276:immunology / Q000628:therapy; D008297:Male; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000628:therapy; D009930:Organic Chemicals / Q000008:administration & dosage / Q000627:therapeutic use; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D019076:Transgenes / Q000235:genetics*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014777:Virus Diseases / Q000276:immunology / Q000517:prevention & control / Q000821:virology
chemical_list: D009930:Organic Chemicals; D053453:Caspase 9; C423866:AP 1903 reagent
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