title: Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation.
abstract: Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Borchers
authors.forename: Elena
authors.initials: E
authors.lastname: Provasi
authors.forename: Anna
authors.initials: A
authors.lastname: Silvani
authors.forename: Marina
authors.initials: M
authors.lastname: Radrizzani
authors.forename: Claudia
authors.initials: C
authors.lastname: Benati
authors.forename: Elke
authors.initials: E
authors.lastname: Dammann
authors.forename: Annika
authors.initials: A
authors.lastname: Krons
authors.forename: Julia
authors.initials: J
authors.lastname: Kontsendorn
authors.forename: Joerg
authors.initials: J
authors.lastname: Schmidtke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kuehnau
authors.forename: Nils
authors.initials: N
authors.lastname: von Neuhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Bernd
authors.initials: B
authors.lastname: Hertenstein
authors.forename: Eva M
authors.initials: EM
authors.lastname: Weissinger
mesh_terms: D000328:Adult; D046528:Chimerism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005822:Genetic Vectors; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007165:Immunosuppression Therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D017708:Leukocyte Transfusion; D008297:Male; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012074:Remission Induction; D012190:Retroviridae / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014019:Tissue Donors; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D013937:Thymidine Kinase; D016044:Fusion Proteins, bcr-abl