title: Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation.
abstract: Poor T lymphocyte reconstitution limits the use of haploidentical stem cell transplantation (SCT) because it results in a high mortality from viral infections. One approach to overcome this problem is to infuse donor T cells from which alloreactive lymphocytes have been selectively depleted, but the immunologic benefit of this approach is unknown. We have used an anti-CD25 immunotoxin to deplete alloreactive lymphocytes and have compared immune reconstitution after allodepleted donor T cells were infused at 2 dose levels into recipients of T-cell-depleted haploidentical SCT. Eight patients were treated at 10(4) cells/kg/dose, and 8 patients received 10(5) cells/kg/dose. Patients receiving 10(5) cells/kg/dose showed significantly improved T-cell recovery at 3, 4, and 5 months after SCT compared with those receiving 10(4) cells/kg/dose (P < .05). Accelerated T-cell recovery occurred as a result of expansion of the effector memory (CD45RA(-)CCR-7(-)) population (P < .05), suggesting that protective T-cell responses are likely to be long lived. T-cell-receptor signal joint excision circles (TRECs) were not detected in reconstituting T cells in dose-level 2 patients, indicating they are likely to be derived from the infused allodepleted cells. Spectratyping of the T cells at 4 months demonstrated a polyclonal Vbeta repertoire. Using tetramer and enzyme-linked immunospot (ELISPOT) assays, we have observed cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-specific responses in 4 of 6 evaluable patients at dose level 2 as early as 2 to 4 months after transplantation, whereas such responses were not observed until 6 to 12 months in dose-level 1 patients. The incidence of significant acute (2 of 16) and chronic graft-versus-host disease (GVHD; 2 of 15) was low. These data demonstrate that allodepleted donor T cells can be safely used to improve T-cell recovery after haploidentical SCT and may broaden the applicability of this approach.
authors.affiliation: Department of Bone Marrow Transplantation, Great Ormond St Childrens Hospital, London WC1N 3JH, United Kingdom. amrolp1@gosh.nhs.uk
authors.forename: Persis J
authors.initials: PJ
authors.lastname: Amrolia
authors.forename: Giada
authors.initials: G
authors.lastname: Muccioli-Casadei
authors.forename: Helen
authors.initials: H
authors.lastname: Huls
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: April
authors.initials: A
authors.lastname: Durett
authors.forename: Adrian
authors.initials: A
authors.lastname: Gee
authors.forename: Eric
authors.initials: E
authors.lastname: Yvon
authors.forename: Heidi
authors.initials: H
authors.lastname: Weiss
authors.forename: Mark
authors.initials: M
authors.lastname: Cobbold
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Cliona
authors.initials: C
authors.lastname: Rooney
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kuehnle
authors.forename: Victor
authors.initials: V
authors.lastname: Ghetie
authors.forename: John
authors.initials: J
authors.lastname: Schindler
authors.forename: Robert
authors.initials: R
authors.lastname: Krance
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
authors.forename: Ellen
authors.initials: E
authors.lastname: Vitetta
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004306:Dose-Response Relationship, Immunologic; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods*; D017053:Infection Control; D008212:Lymphocyte Depletion; D008875:Middle Aged; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous