Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation.
Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginning approximately 36 hours after the marrow infusion was completed. Fourteen (40%) of the 35 patients who could be evaluated developed grade III or IV GVHD. In a contemporaneous population of 121 patients who received marrow from HLA-matched unrelated donors and were given methotrexate and cyclosporine without the immunotoxin, the incidence of grades III and IV GVHD was 24%. Cyclosporine blocked the induction of CD25 expression on alloactivated T cells in vitro but had no detectable effect on CD25 expression by T-regulatory cells. Taken together, these results are consistent with the hypothesis that cyclosporine protected alloactivated donor T cells from the effects of the immunotoxin, whereas the CD25+ T-regulatory cells remained susceptible, causing an unexpected exacerbation of acute GVHD.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. pmartin@fhcrc.org
Paul J
PJ
Martin
Ji
J
Pei
Ted
T
Gooley
Claudio
C
Anasetti
Frederick R
FR
Appelbaum
Joachim
J
Deeg
John A
JA
Hansen
Richard A
RA
Nash
Effie W
EW
Petersdorf
Rainer
R
Storb
Victor
V
Ghetie
John
J
Schindler
Ellen S
ES
Vitetta
D000328:Adult; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D016026:Bone Marrow Transplantation / Q000276:immunology*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D006680:HLA Antigens / Q000032:analysis / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018796:Immunoconjugates; D007422:Intestines / Q000473:pathology; D007938:Leukemia / Q000628:therapy; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D008223:Lymphoma / Q000628:therapy; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D012276:Ricin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D012867:Skin / Q000473:pathology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D018796:Immunoconjugates; C114847:RFT5-SMPT-dgA immunotoxin; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D012276:Ricin