title: Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft.
abstract: Administration of donor T cells expressing the herpes simplex-thymidine kinase (HS-tk) with a hematopoietic stem cell (HSC) transplantation could allow, if graft-versus-host disease (GVHD) was to occur, a selective in vivo depletion of these T cells by the use of ganciclovir (GCV). The study evaluates the feasibility of such an approach. Escalating numbers of donor HS-tk-expressing CD3(+) gene-modified cells (GMCs) are infused with a T-cell-depleted bone marrow transplantation (BMT). Twelve patients with hematological malignancies received 2 x 10(5) (n = 5), 6 x 10(5) (n = 5), or 20 x 10(5) (n = 2) donor CD3(+) GMCs/kg with a BMT from a human leukocyte antigen (HLA)-identical sibling. No acute toxicity was associated with GMC administration. An early increase of circulating GMCs followed by a progressive decrease and long-lasting circulation of GMCs was documented. GCV treatment resulted in significant rapid decrease in circulating GMCs. Three patients developed acute GVHD, with a grade of at least II, while one patient developed chronic GVHD. Treatment with GCV alone was associated with a complete remission (CR) in 2 patients with acute GVHD, while the addition of glucocorticoids was necessary to achieve a CR in the last case. Long-lasting CR occurred with GCV treatment in the patient with chronic GVHD. Unfortunately, Epstein-Barr virus-lymphoproliferative disease occurred in 3 patients. Overall, the administration of low numbers of HS-tk-expressing T cells early following an HLA-identical BMT is associated with no acute toxicity, persistent circulation of the GMCs, and GCV-sensitive GVHD. Such findings open the way to the infusion of higher numbers of gene-modified donor T cells to enhance post-BMT immune competence while preserving GCV-sensitive alloreactivity.
authors.affiliation: Etablissement Français du Sang, Bourgogne/Franche-Comté, and Service d'Anatomie Pathologique and Service d'Hématologie, Centre Hospitolier Universitoire (CHU) Besançon, Besançon, France. pierre.tiberghien@univ-fcomte.fr
authors.forename: P
authors.initials: P
authors.lastname: Tiberghien
authors.forename: C
authors.initials: C
authors.lastname: Ferrand
authors.forename: B
authors.initials: B
authors.lastname: Lioure
authors.forename: N
authors.initials: N
authors.lastname: Milpied
authors.forename: R
authors.initials: R
authors.lastname: Angonin
authors.forename: E
authors.initials: E
authors.lastname: Deconinck
authors.forename: J M
authors.initials: JM
authors.lastname: Certoux
authors.forename: E
authors.initials: E
authors.lastname: Robinet
authors.forename: P
authors.initials: P
authors.lastname: Saas
authors.forename: B
authors.initials: B
authors.lastname: Petracca
authors.forename: C
authors.initials: C
authors.lastname: Juttner
authors.forename: C W
authors.initials: CW
authors.lastname: Reynolds
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: P
authors.initials: P
authors.lastname: Hervé
authors.forename: J Y
authors.initials: JY
authors.lastname: Cahn
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D017252:CD3 Complex; D018929:Cell Culture Techniques; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control / Q000628:therapy; D006561:Herpes Simplex / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods*; D008232:Lymphoproliferative Disorders / Q000821:virology; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000637:transplantation* / Q000821:virology; D013937:Thymidine Kinase / Q000008:administration & dosage* / Q000187:drug effects / Q000235:genetics / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection; D014184:Transplantation, Homologous / Q000379:methods; D016896:Treatment Outcome; D014764:Viral Proteins / Q000187:drug effects / Q000235:genetics / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D017252:CD3 Complex; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir