Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions.
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.


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 x 10(6) 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 x 10(6) CD4(+) and 9.7 x 10(6) 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.


CONCLUSIONS
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.
Burt
Richard K
RK
Northwestern University School of Medicine, Division of Immunotherapy, Chicago, Illinois 60611, USA. rburt@nwu.edu
Drobyski
William R
WR
Seregina
Tatiana
T
Traynor
Ann
A
Oyama
Yu
Y
Keever-Taylor
Carolyn
C
Stefka
Jacob
J
Kuzel
Timothy M
TM
Brush
Mary
M
Rodriquez
Julianne
J
Burns
Willam
W
Tennant
Lucinda
L
Link
Charles
C
D006086:Graft vs Host Disease / Q000209:etiology; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014019:Tissue Donors; D014161:Transduction, Genetic; D014184:Transplantation, Homologous
D013937:Thymidine Kinase