TY - JOUR
T1 - Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions
AU - Burt, Richard K.
AU - Drobyski, William R.
AU - Seregina, Tatiana
AU - Traynor, Ann
AU - Oyama, Yu
AU - Keever-Taylor, Carolyn
AU - Stefka, Jacob
AU - Kuzel, Timothy M.
AU - Brush, Mary
AU - Rodriquez, Julianne
AU - Burns, Willam
AU - Tennant, Lucinda
AU - Link, Charles
N1 - Funding Information:
This research was supported by a grant from the Leukemia Society of America and from the Iowa Methodist Medical Center. We thank A.D. Miller for supplying the LXSN vector and the PA317 vector producer cells.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - Objective. Donor lymphocytes mediate both a beneficial graft-vs-leukemia/lymphoma (GVL) effect as well as graft-vs-host disease (GVHD), the most dreaded complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transduction of donor lymphocytes with a herpes simplex thymidine kinase (HSVtk) gene prior to infusion confers lethal sensitivity to the anti-herpes drug, ganciclovir (GCV). HSVtk-transduced donor lymphocyte infusions (DLI) have already been used and significant problems have limited the clinical experience to very few patients. To this end, we also report on a study of whether HSVtk-DLI induces GVHD/GVL and if infusion of GCV allows abrogation of GVHD by selective killing of donor lymphocytes. Materials and Methods. Nine patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were infused with HSVtk gene-modified donor lymphocytes. In brief, transgeneic lymphocytes were prepared by 3 days of activation, 1 day of transduction, 6 days of selection with G418, and 2 to 4 weeks of expansion. Results. From 5.0 to 199 × 106 CD3+ DLI were infused. There were no toxicities and no correlation between CD3+ cell dose and either GVHD or GVL was observed. Only one patient who had cutaneous T-cell lymphoma (CTCL) developed GVHD and that same patient is the only patient to have an anti-tumor response. The patient was infused with 23 × 106 CD4+ and 9.7 × 106 CD8+ HSVtk DLI. Following discontinuation of immune suppression and infusion of GCV, GVHD promptly resolved. Although the CTCL relapsed, it has been easily controlled with intermittent topical therapy. One patient with acute myelogenous leukemia (AML) had a remission inversion of undetermined significance. Two patients with AML, one patient with lymphoma, and four patients with chronic myelogenous leukemia (CML) did not respond. Conclusion. HSVtk-DLI may provide an anti-tumor effect in vivo and may induce GVHD that is abrogated by GCV treatment. While technical aspects to improve response need to be perfected, HSVtk-DLI infusion to induce a transient GVL/ GVHD may become an effective future therapy to minimize complications of allogeneic HSCT.
AB - Objective. Donor lymphocytes mediate both a beneficial graft-vs-leukemia/lymphoma (GVL) effect as well as graft-vs-host disease (GVHD), the most dreaded complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transduction of donor lymphocytes with a herpes simplex thymidine kinase (HSVtk) gene prior to infusion confers lethal sensitivity to the anti-herpes drug, ganciclovir (GCV). HSVtk-transduced donor lymphocyte infusions (DLI) have already been used and significant problems have limited the clinical experience to very few patients. To this end, we also report on a study of whether HSVtk-DLI induces GVHD/GVL and if infusion of GCV allows abrogation of GVHD by selective killing of donor lymphocytes. Materials and Methods. Nine patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were infused with HSVtk gene-modified donor lymphocytes. In brief, transgeneic lymphocytes were prepared by 3 days of activation, 1 day of transduction, 6 days of selection with G418, and 2 to 4 weeks of expansion. Results. From 5.0 to 199 × 106 CD3+ DLI were infused. There were no toxicities and no correlation between CD3+ cell dose and either GVHD or GVL was observed. Only one patient who had cutaneous T-cell lymphoma (CTCL) developed GVHD and that same patient is the only patient to have an anti-tumor response. The patient was infused with 23 × 106 CD4+ and 9.7 × 106 CD8+ HSVtk DLI. Following discontinuation of immune suppression and infusion of GCV, GVHD promptly resolved. Although the CTCL relapsed, it has been easily controlled with intermittent topical therapy. One patient with acute myelogenous leukemia (AML) had a remission inversion of undetermined significance. Two patients with AML, one patient with lymphoma, and four patients with chronic myelogenous leukemia (CML) did not respond. Conclusion. HSVtk-DLI may provide an anti-tumor effect in vivo and may induce GVHD that is abrogated by GCV treatment. While technical aspects to improve response need to be perfected, HSVtk-DLI infusion to induce a transient GVL/ GVHD may become an effective future therapy to minimize complications of allogeneic HSCT.
UR - http://www.scopus.com/inward/record.url?scp=0141596016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141596016&partnerID=8YFLogxK
U2 - 10.1016/S0301-472X(03)00226-1
DO - 10.1016/S0301-472X(03)00226-1
M3 - Article
C2 - 14550806
AN - SCOPUS:0141596016
SN - 0301-472X
VL - 31
SP - 903
EP - 910
JO - Experimental Hematology
JF - Experimental Hematology
IS - 10
ER -
