title: Facilitating T-cell immune reconstitution after haploidentical transplantation in adults.
abstract: Delayed reconstitution of cellular immunity following T-cell-depleted, CD34-enriched, allogeneic hematopoietic progenitor cell transplantation (HPCT) is the major cause of morbidity and mortality following haploidentical transplantation in adults. This is illustrated in our recent study of 28 high-risk adult patients (median age 31) who were treated with conditioning regimens containing antithymocyte globulin (ATG) before T-cell-depleted, CD34-enriched allogeneic HPCT. Overall mortality was 93% (26/28 patients) with a median survival of 4 months posttransplant. Poor cellular immune reconstitution contributed to death of 21/28 patients, with eight deaths due to opportunistic infections and seven deaths due to relapse. While recovery of normal numbers of circulating NK cells and B-cells occurred within the first 1-2 months posttransplant, recovery of normal numbers of blood T-cells was suppressed for more than 1 year. The mean half-life of active ATG levels in serum was 6 days; rapid clearance suggested that residual ATG did not contribute to the delay of posttransplant T-cell reconstitution. Rapid T-cell reconstitution was seen only in younger patients, indicating that poor thymic function and the absence of T-cells in the graft are the major causes of delayed recovery of cellular immunity. Improved cellular immunity after T-cell-depleted haploidentical HPCT will thus require novel strategies to adoptively transfer antigen specific donor T-cells without inducing lethal graft-versus-host disease (GvHD). This problem has been addressed in a preclinical murine model of MHC-mismatched bone marrow transplantation. Donor T-cells treated ex vivo with fludarabine or a UVA light-activated psoralen compound (amotosalen) have a markedly reduced ability to induce GvHD, yet the treated T-cells confer protection against murine cytomegalovirus and an infused leukemic cell line. Polyclonal donor T-cells reconstituted the blood and lymphoid compartments posttransplant and expanded in vivo. Derivatives of ex-vivo-treated donor T-cells retained the ability to produce cytokines and proliferate in response to antigen challenge. The mechanism of reduced GvHD potential of ex-vivo-treated T-cells appears to be selection of a subset of memory donor T-cells that do not initially home to secondary lymphoid organs and have reduced capacity for producing inflammation in the immediate posttransplant period. Direct selection of the memory subset by high-speed FACS confirmed the improved therapeutic index in the murine model system. Preclinical data indicate the feasibility of treating human T-cells with fludarabine, psoralen, or direct selection based upon the memory phenotype to efficiently produce a population of polyclonal donor T-cells with reduced GvHD activity. A planned clinical phase 1 trial of adoptive therapy utilizing ex vivo psoralen-treated donor T-cells in recipients of T-cell-depleted haploidentical HPCT is presented.
authors.affiliation: Division of Hematology-Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. ewaller@emory.edu
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Giver
authors.forename: Hilary
authors.initials: H
authors.lastname: Rosenthal
authors.forename: Jyoti
authors.initials: J
authors.lastname: Somani
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Langston
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: John D
authors.initials: JD
authors.lastname: Roback
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.forename: Istvan
authors.initials: I
authors.lastname: Redei
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods* / Q000401:mortality; D008297:Male; D051379:Mice; D013601:T-Lymphocytes; D019172:Transplantation Conditioning / Q000379:methods / Q000401:mortality*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous