title: Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation.
abstract: The infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene (TK-cells) is a promising strategy for the treatment of hematologic malignancies relapsing after allogeneic hematopoietic stem cell transplantation. Here we report the results of a phase I clinical trial designed to examine the feasibility, safety, and efficacy of donor lymphocyte infusion (DLI) of TK-cells. Three patients (two with malignant lymphomas, one with acute myeloid leukemia) were enrolled in the trial and received a single DLI of 1 × 10(7) or 5 × 10(7) TK-cells/kg. No local or systemic toxicity related to the gene-transfer procedure was observed. Two patients achieved stable disease. No patient had severe graft-versus-host disease requiring systemic steroid and/or ganciclovir administration. TK-cells were detected in the peripheral blood of all three patients by PCR, but did not persist longer than 28 days. Analysis of cytotoxic T lymphocyte activity detected no immune response against TK-cells by the recipient's own T cells. Flow cytometric analysis showed low proliferative activity and cytotoxic function of TK-cells. In conclusion, DLI of TK-cells was safely performed in all three patients. Our analysis suggests the probable cause of rapid disappearance of TK-cells to be insufficient in vivo expansion of TK-cells in these patients.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ueda
authors.forename: Ayumu
authors.initials: A
authors.lastname: Ito
authors.forename: Kohei
authors.initials: K
authors.lastname: Tada
authors.forename: Shigeo
authors.initials: S
authors.lastname: Fuji
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomura
authors.forename: Ikuei
authors.initials: I
authors.lastname: Nukaya
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Mori
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takaue
authors.forename: Yuji
authors.initials: Y
authors.lastname: Heike
mesh_terms: D000328:Adult; D015415:Biomarkers; D002470:Cell Survival / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000628:therapy; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D013937:Thymidine Kinase; D015774:Ganciclovir