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Kinetics of In Vivo Elimination of Suicide Gene-Expressing T Cells Affects Engraftment, Graft-versus-Host Disease, and Graft-versus-Leukemia after Allogeneic Bone Marrow Transplantation¹

Michael P. Rettig^*, Julie K. Ritchey^*, Julie L. Prior^,, Jeffrey S. Haug^*, David Piwnica-Worms^, and John F. DiPersio^2,*

^* Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110; and Molecular Imaging Center, Mallinckrodt Institute of Radiology, and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110

Suicide gene therapy is one approach being evaluated for the control of graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We recently constructed a novel chimeric suicide gene in which the entire coding region of HSV thymidine kinase (HSV-tk) was fused in-frame to the extracellular and transmembrane domains of human CD34 (CD34-tk). CD34-tk is an attractive candidate as a suicide gene in man because of the ensured expression of HSV-tk in all selected cells and the ability to rapidly and efficiently purify gene-modified cells using clinically approved CD34 immunoselection techniques. In this study we assessed the efficacy of the CD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express CD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that CD34-tk-expressing T cells could be purified to near homogeneity by CD34 immunoselection and selectively eliminated ex vivo and in vivo when exposed to low concentrations of GCV. The optimal time to administer GCV after allogeneic BMT with CD34-tk-expressing transgenic T cells was dependent on the intensity of the conditioning regimen, the leukemic status of the recipient, and the dose and timing of T cell infusion. Importantly, we used a controlled graft-vs-host reaction to promote alloengraftment in sublethally irradiated mice and provide a graft-vs-leukemia effect in recipients administered a delayed infusion of CD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of CD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.