Use of an anti-pan T-lymphocyte ricin a chain immunotoxin in steroid-resistant acute graft-versus-host disease.
Acute steroid-resistant graft-versus-host disease (AGVHD) after allogeneic bone marrow transplantation is frequently fatal. A new treatment for this T-lymphocyte-mediated condition uses an immunotoxin, H65-RTA, comprised of a monoclonal antibody that recognizes the CD5 lymphocyte differentiation antigen coupled to ricin A chain, a cytotoxic enzyme that inhibits protein synthesis. The safety and efficacy of this lymphocyte-targeted immunotoxin was evaluated in patients with severe AGVHD in a phase I-II dose escalation study with group expansion at the two middle doses. Thirty-four patients received up to 14 daily intravenous infusions of the immunotoxin. The principal side effects were constitutional symptoms such as fatigue and myalgias, and hypoalbuminemia with weight gain was seen at all doses. Thirty-two patients were evaluated for improvement or resolution of disease. Durable complete or partial responses were not dose-related and were seen in 16 patients. Skin GVHD had the highest incidence of response (73%), although improvement or resolution in gastrointestinal tract (45%) and liver (28%) GVHD was also noted. Survival in responding patients was significantly prolonged at all times as compared with those with no response (P = .03). Treatment was associated with a rapid decrease in peripheral blood T lymphocytes, which persisted for greater than 1 month after therapy. Anti-immunotoxin antibodies were seen in 6 of the 23 patients tested; these were of low titer and did not block immunotoxin binding to T cells. Results of this study indicate that anti-T-lymphocyte immunotoxins may form a new class of immunosuppressive agents useful in T-lymphocyte-mediated diseases.
Byers
V S
VS
XOMA Corporation, Berkeley, CA 94710.
Henslee
P J
PJ
Kernan
N A
NA
Blazar
B R
BR
Gingrich
R
R
Phillips
G L
GL
LeMaistre
C F
CF
Gilliland
G
G
Antin
J H
JH
Martin
P
P
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000917:Antibody Formation; D016026:Bone Marrow Transplantation / Q000276:immunology; D002986:Clinical Trials as Topic; D004351:Drug Resistance; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D000922:Immunotoxins / Q000097:blood / Q000627:therapeutic use*; D007938:Leukemia / Q000601:surgery; D008223:Lymphoma / Q000601:surgery; D046911:Macromolecular Substances; D008297:Male; D009101:Multiple Myeloma / Q000601:surgery; D012276:Ricin / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D046911:Macromolecular Substances; D012276:Ricin