title: Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.
abstract: To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/Rimiducid). All patients receiving >10(4) alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3(+)CD19(+) T cells within 30 minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs of GVHD-associated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial was registered at www.clinicaltrials.gov as #NCT01494103.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Caridad A
authors.initials: CA
authors.lastname: Martinez
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Swati
authors.initials: S
authors.lastname: Naik
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Rammurti T
authors.initials: RT
authors.lastname: Kamble
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: April G
authors.initials: AG
authors.lastname: Durett
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Olga
authors.initials: O
authors.lastname: Dakhova
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stasi
authors.affiliation: Bellicum Pharmaceuticals, Inc., Houston, TX; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Lin
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: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Bambi J
authors.initials: BJ
authors.lastname: Grilley
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX;
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000293:Adolescent; D053453:Caspase 9 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009930:Organic Chemicals / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000637:transplantation*; D055815:Young Adult
chemical_list: D009930:Organic Chemicals; C506433:CASP9 protein, human; D053453:Caspase 9; C423866:AP 1903 reagent