title: Induction of early post-transplant graft-versus-leukemia effects using intentionally mismatched donor lymphocytes and elimination of alloantigen-primed donor lymphocytes for prevention of graft-versus-host disease.
abstract: Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmyeloablative conditioning. GVL effects can be amplified by post-grafting donor lymphocyte infusion (DLI). Unfortunately, DLI is frequently associated with graft-versus-host disease (GVHD). We investigated the feasibility of induction of potent GVL effects by DLI using intentionally mismatched lymphocytes followed by elimination of alloreactive donor T cells by cyclophosphamide for prevention of lethal GVHD following induction of very short yet most potent GVL effects. Mice inoculated with B-cell leukemia (BCL1) and mismatched donor lymphocytes were treated 2 weeks later with low-dose or high-dose cyclophosphamide. All mice receiving cyclophosphamide 2 weeks after DLI survived GVHD, and no residual disease was detected by PCR; all control mice receiving DLI alone died of GVHD. Analysis of host (female) and donor (male) DNA showed that cyclophosphamide treatment eradicated most alloreactive donor cells, yet mixed chimerism was converted to full donor chimerism following transient self-limited GVHD. Our working hypothesis suggests that short-term yet effective and safe adoptive immunotherapy of leukemia may be accomplished early post-transplantation using alloreactive donor lymphocytes, with prevention of GVHD by elimination of GVL effector cells.
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Cell Therapy and Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Yang
authors.forename: Iris
authors.initials: I
authors.lastname: Yung
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.forename: Ali
authors.initials: A
authors.lastname: Abdul-Hai
authors.forename: Judith
authors.initials: J
authors.lastname: Kasir
authors.forename: Shoshana
authors.initials: S
authors.lastname: Reich
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007519:Isoantigens / Q000276:immunology*; D015448:Leukemia, B-Cell / Q000276:immunology* / Q000628:therapy*; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018365:Neoplasm, Residual; D018183:Transplantation Chimera
chemical_list: D007166:Immunosuppressive Agents; D007519:Isoantigens; D003520:Cyclophosphamide