title: Long term follow up of patients after allogeneic stem cell transplantation and transfusion of HSV-TK transduced T-cells.
abstract: Allogeneic stem cell transplantation (allo-HSCT) is one of the curative treatments for hematologic malignancies, but is hampered by severe complications, such as acute or chronic graft-versus-host-disease (aGvHD; cGvHD) and infections. CD34-selection of stem cells reduces the risk of aGvHD, but also leads to increased infectious complications and relapse. Thus, we studied the safety, efficacy, and feasibility of transfer of gene modified donor T-cells shortly after allo-HSCT in two clinical trials between 2002 and 2007 and here we compare the results to unmodified donor leukocyte infusion (DLI). The aim of these trials was to provide patients with the protection of T-cells after T-cell-depleted allo-HSCT in the matched or mismatched donor setting with an option to delete transduced T-cells, if severe aGvHD occurred within the trial period. Donor-T-cells were transduced with the replication-deficient retrovirus SFCMM-3, expressing HSV-TK and the truncated ΔLNGFR for selection of transduced cells. Transduced cells were transfused either after day +60 (matched donors) or on day +42 (haploidentical donors). Nine patients were included in the first trial (MHH; 2002 until 2007), two were included in TK007 (2005-2009) and six serves as a control group for outcome after haploidentical transplantation without HSV-TK-transduced DLI. Three patients developed acute GvHD, two had grade I of the skin, one had aGvHD on day +131 (post-HSCT; +89 post-HSV-TK DLI) grade II, which was successfully controlled by ganciclovir (GCV). Donor chimerism was stabilized after transfusion of the transduced cells in all patients treated. Functionality of HSV-TK gene expressing T-cells was shown by loss of bcr-able gene expression as well as by control of cytomegalovirus-reactivation. To date, six patients have relapsed and died, two after a second hematopoietic stem cell transplantation without T-cell depletion or administration of unmodified T-cells. Eleven patients (seven post-HSV-TK DLI) are alive and well to date.
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Weissinger
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Borchers
authors.affiliation: MolMed, Milano Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Silvani
authors.affiliation: Cancer Immunotherapy and Gene Therapy Program, San Raffaele Hospital Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Provasi
authors.affiliation: MolMed, Milano Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Radrizzani
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Beckmann
authors.affiliation: MolMed, Milano Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Benati
authors.affiliation: Institute of Human Genetics, Hannover Medical School Hannover, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Schmidtke
authors.affiliation: Institute of Human Genetics, Hannover Medical School Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kuehnau
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schweier
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Luther
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Fernandez-Munoz
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Beutel
authors.affiliation: Cancer Immunotherapy and Gene Therapy Program, San Raffaele Hospital Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: Cancer Immunotherapy and Gene Therapy Program, San Raffaele Hospital Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany ; Department of Hematology/Oncology, Klinikum Bremen-Mitte Bremen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hertenstein
authors.affiliation: Laboratory for Transplantation Biology, Department of Hematology/Hemostasis/Oncology/Stem Cell Transplantation, Hannover Medical School Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
keywords: allogeneic stem cell transplantation; gene therapy; gene transfer; graft vs. host disease; horizontal; proteomics data