Control of graft-versus-host disease with maintenance of the graft-versus-leukemia effect in a murine allogeneic transplant model using retrovirally transduced murine suicidal lymphocytes.
OBJECTIVE
Limited clinical trials have validated the hypothesis of controlling graft-versus-host disease (GVHD) arising from stem cell transplant utilizing suicidal T-lymphocytes that have been transduced to express the HSV-TK gene. However, clinical utility has been limited by diminished T-cell function arising from the production process. To evaluate strategies for harnessing the graft-versus-leukemia (GVL) effect while improving the safety and function of suicidal lymphocytes, we have developed techniques to produce fully functional, retrovirally transduced, HSV-TK-positive murine T cells (TK+TC).


METHODS
Utilizing a murine major histocompatibility complex-matched transplant model, we evaluated the ability of TK+TC to generate a GVL effect and the ability to control GVHD in experiments where we varied the dose of TK+TC, ganciclovir (GCV) dose, the start of GCV administration (day 4, 7, 10, 13, 15, or 19) posttransplantation, and the GCV administration route (osmotic pump versus intraperitoneal).


RESULTS
At TK+TC doses in excess of the standard lethal dose (SLD) of unmanipulated T-cells, GCV administration completely (2 x SLD) and partially (4 x SLD) controlled GVHD. Additionally, GVHD remained reversible despite delaying administration of GCV for a week after GVHD developed. Importantly, GVHD was controlled with a 1-log but not 2-log reduction in GCV dose, and this "partial suicide" preserved more circulating TK+TC compared with standard-dose GCV. Survival of leukemia-positive mice receiving TK+TC and GCV was significantly increased compared with control cohorts not receiving GCV or transplanted with unmanipulated T cells, thereby demonstrating a GVL effect.


CONCLUSIONS
Retrovirally transduced suicidal lymphocytes generate a potent GVL effect while simultaneously enabling control of GVHD, which results in improved leukemia and GVHD-free survival.
Kornblau
Steven M
SM
Department of Blood and Marrow Transplantation, Unit 448, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA. skornbla@mdanderson.org
Aycox
Preston G
PG
Stephens
Clifton
C
McCue
L David
LD
Champlin
Richard E
RE
Marini
Frank C
FC
D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014161:Transduction, Genetic; D014184:Transplantation, Homologous
D016207:Cytokines; D015774:Ganciclovir