Leucyl-leucine methyl ester-treated haploidentical donor lymphocyte infusions can mediate graft-versus-leukemia activity with minimal graft-versus-host disease risk.
L-leucyl-L-leucine methyl ester (LLME) prevents GVHD in several animal models by depleting dipeptidyl peptidase I (DPPI)-expressing cytotoxic cellular subsets. However, clinical application has been hampered by difficulties in stem cell engraftment following treatment of donor bone marrow inocula with LLME at the concentrations necessary to purge DPPI-expressing T-cells. Noting that T-cells can mediate graft-versus-leukemia (GVL) responses via both perforin (usually co-expressed in cytotoxic granules with DPPI) and Fas ligand pathways in a murine model, we hypothesized that LLME might be useful for treatment of delayed DLIs for potential GVL activity with a decreased risk of GVHD induction. In regard to the clinical setting, the ex vivo use of LLME for this purpose would circumvent any toxicity issues for donor stem cells, because by that time patients would have already achieved successful engraftment. For our preclinical studies, we used the haploidentical C57BL/6 (B6) (H2b) --> ((B6 x DBA/2)F1 (H(2b/d)) murine model with lethally irradiated hosts that had received transplants of T-cell-depleted bone marrow cells and were challenged with the MMD2-8 myeloid leukemia line (H2d) of DBA/2 origin. A DLI of LLME-treated donor splenocytes, from B6 mice presensitized to recipient alloantigens, was administered in varying doses 14 days post-marrow transplantation, and the potential for both GVHD and GVL activity was assessed. All mice that received any dose of LLME-treated DLI survived indefinitely, without evidence of cachexia nor B-cell hypoplasia, in contrast to the severe and lethal GVHD induced by mock-treated DLI. Histological analysis largely correlated with the symptomatic findings and revealed no GVHD-like lesions in the spleens of LLME-treated DLI recipients, although some mice displayed various degrees of hepatic mononuclear infiltration. Most notably, mice given LLME-treated DLI also experienced DLI dose-dependent increases in survival against the challenge with the MMD2-8 leukemia. LLME-treated splenocytes remained immunocompetent, as these cells could proliferate in response to mitogens and to restimulation with ovalbumin when used as a recall antigen. In conclusion, LLME-treated DLI possesses immune potential and, in particular, GVL activity without inducing clinically evident GVHD.
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Michael H
MH
Hsieh
Gabor
G
Varadi
Neal
N
Flomenberg
Robert
R
Korngold
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods; D004151:Dipeptides / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000473:pathology / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D006239:Haplotypes; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D017710:Lymphocyte Transfusion / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012306:Risk; D014181:Transplantation Immunology / Q000187:drug effects*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D004151:Dipeptides; D007166:Immunosuppressive Agents; C045139:leucyl-leucine-methyl ester