Elimination of leukemia in the absence of lethal graft-versus-host disease after allogenic bone marrow transplantation.
Donor T cells are able to effect a graft-vs-leukemia (GVL) response but also induce graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation. We used an AKR leukemia murine transplant model, analogous to human acute lymphoblastic leukemia, in which donor T cells expressed a thymidine kinase suicide gene, to test whether separation of GVL and graft-vs-host (GVH) responses was feasible by selectively eliminating alloactivated donor T cells at defined time points posttransplant. Under experimental conditions where untreated mice could not be cured of disease without dying from GVHD, mice transplanted with thymidine kinase-positive T cells and subsequently administered ganciclovir (GCV) could eliminate leukemia without lethal GVHD. Timing of GCV administration, donor T cell dose, and preexisting leukemia burden were observed to be critical variables. Eradication of leukemia without lethal GVHD in GCV-treated mice implied that the kinetics of GVL and GVH responses were asynchronous and could therefore be temporally dissociated by timely GCV administration. That this strategy was feasible in a murine leukemia model in which GVHD and GVL reactivity are tightly linked suggests that this approach may be relevant to the treatment of selected human leukemias where similar constraints exist. This strategy represents an alternative approach to separating GVL and GVH reactivity and challenges the current paradigm that separation of these responses is dependent upon the administration of donor T cells with restricted specificity for leukemia as opposed to host Ags.
Drobyski
William R
WR
Bone Marrow Transplant Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. bill@bmt.mcw.edu
Gendelman
Maria
M
Vodanovic-Jankovic
Sanja
S
Gorski
Jack
J
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D015774:Ganciclovir / Q000008:administration & dosage; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality*; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology; D007274:Injections, Intraperitoneal; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D013937:Thymidine Kinase / Q000096:biosynthesis; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase; D015774:Ganciclovir