Successful treatment of human acute T-cell leukemia in SCID mice using the anti-CD7-deglycosylated ricin A-chain immunotoxin DA7.
The study of new therapeutic approaches for refractory human leukemia has been hampered by the lack of relevant in vivo models with disseminated disease, particularly T acute lymphoblastic leukemia (T-ALL). In the present study we evaluated methods for establishing and therapy of a human T-ALL cell line (MT-ALL) in 73 SCID mice. MT-ALL is a T-cell receptor alpha/beta +, CD3+, and CD7+ leukemia cell line, derived from a patient with refractory disease and early death. Injection of 5 x 10(7) MT-ALL cells i.v. caused disseminated human leukemia in hematopoietic and nonhematopoietic organs in 100% of SCID mice (n = 9) leading to death or terminal disease at 65 to 70 days after a uniform clinical course. To study possible therapeutic approaches for disseminated leukemia we utilized an immunotoxin, DA7, constructed by chemically linking the mouse IgG2b anti-CD7(3A1E) monoclonal antibody which recognizes a pan-T-cell marker expressed on almost all T-cell leukemias to deglycosylated ricin A-chain, a catalytic plant toxin and inhibitor of protein synthesis. Administration of DA7 led to greater than 5 log kill of clonogenic MT-ALL cells in vitro and selectively inhibited protein synthesis. DA7 was administered to mice at a dose of 10 micrograms/mouse/day for 5 consecutive days starting 8 days after i.v. inoculation of leukemia. The immunotoxin therapy resulted in significant long term survival over 348 days compared to untreated or control mice treated with anti-CD7 antibody and deglycosylated ricin A-chain which were all dead by day 70 (P less than 0.001). Even after more than 11 months there was no evidence of disease in 82% of the DA7 treated animals. SCID mice given i.p. injections (n = 9) developed an i.p. tumor mass but demonstrated metastasis outside the peritoneum with disseminated leukemia in hematopoietic and nonhematopoietic organs, a finding different from most conventional nude mouse models. The leukemia was fatal in 100% and killed the animals at 68-95 days. SCID mice given i.p. injections of MT-ALL completely responded to therapy with DA7, resulting in survival of 100% of the animals (n = 10) at 216 days (P less than 0.001 compared to untreated animals). Anti-CD7 antibody, deglycosylated ricin A-chain, and a control anti-melanoma immunotoxin (IND1-RTA) showed no therapeutic effect. We conclude that DA7 is an effective in vivo therapeutic agent against human MT-ALL in the SCID mouse system, suggesting potential usefulness for therapy of humans with poor prognosis T-cell leukemia.
Department of Laboratory Medicine/Pathology, University of Minnesota, Minneapolis 55455.
B
B
Jansen
D A
DA
Vallera
W B
WB
Jaszcz
D
D
Nguyen
J H
JH
Kersey
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D004354:Drug Screening Assays, Antitumor; D006031:Glycosylation; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000627:therapeutic use*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012276:Ricin / Q000737:chemistry / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte; D000922:Immunotoxins; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D012276:Ricin