Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft

Blood. 2001 Jan 1;97(1):63-72. doi: 10.1182/blood.v97.1.63.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacology
  • Bone Marrow Transplantation / immunology
  • Bone Marrow Transplantation / methods*
  • CD3 Complex
  • Cell Culture Techniques
  • Disease-Free Survival
  • Epstein-Barr Virus Infections / complications
  • Female
  • Ganciclovir / administration & dosage
  • Ganciclovir / pharmacology
  • Graft Survival
  • Graft vs Host Disease / prevention & control
  • Graft vs Host Disease / therapy
  • Herpes Simplex / drug therapy
  • Herpes Simplex / enzymology
  • Humans
  • Lymphocyte Depletion / methods*
  • Lymphoproliferative Disorders / virology
  • Male
  • Middle Aged
  • Survival Rate
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / transplantation*
  • T-Lymphocytes / virology
  • Thymidine Kinase / administration & dosage*
  • Thymidine Kinase / drug effects
  • Thymidine Kinase / genetics
  • Thymidine Kinase / therapeutic use
  • Time Factors
  • Transfection
  • Transplantation, Homologous / methods
  • Treatment Outcome
  • Viral Proteins / drug effects
  • Viral Proteins / genetics
  • Viral Proteins / therapeutic use


  • Antiviral Agents
  • CD3 Complex
  • Viral Proteins
  • Thymidine Kinase
  • Ganciclovir