Induction of Graft-versus-Leukemia (GVL) Effect without Graft-versus-Host Disease (GVHD) by Pretransplant Donor Treatment with Immunomodulators

Pretransplant donor treatment with immunomodulators such as complete Freund's adjuvant (CFA) or oligodeoxynucleotide sequences expressing CpG motifs (CpG), was applied in sublethally irradiated host mice inoculated with murine models of mammary carcinoma (4TI) or B cell leukemia (BCLI). Spleen cells or IL-2 activated splenocytes (lymphokine activated killer [LAK]) derived from donor mice treated with CpG emulsified in incomplete Freund's adjuvant (IFA), (CpG + IFA) did not cause graft-versus-host disease (GVHD), but were not efficient enough to induce a significant graft-versus-tumor (GVT) response against 4TI cells. In contrast, an efficient graft-versus-leukemia (GVL) effect was evident in BCLI-bearing mice inoculated with spleen cells from donors pretreated with CFA or CpG + IFA. Pretransplant donor treatment with CFA prolonged survival to a median of 62 days with 3 of 27 mice remaining GVHD- and leukemia-free for >200 days, compared to GVHD-related death of all mice inoculated with naive cells (median 17 days), or leukemia-related death of all mice inoculated with leukemia cells (median of 27 days). Pretransplant donor treatment with CpG + IFA exerted a more efficient GVL effect with reduced GVHD resulting in 12 of 26 GVHD- and leukemia-free survivors for >200 days. Our results suggest that it may be possible to prevent GVHD while sparing an efficient GVL effect by using pretransplant donor treatment with immunomodulators prior to allogeneic stem cell transplantation and/or donor lymphocyte infusions in hematologic malignancies.