Successful treatment of human acute T-cell leukemia in SCID mice using the anti-CD7-deglycosylated ricin A-chain immunotoxin DA7.

Abstract

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.

• Authors: B Jansen, D A Vallera, W B Jaszcz, D Nguyen, J H Kersey
• Journal: Cancer research (Cancer Res) Vol. 52 Issue 5 Pg. 1314-21 (Mar 01 1992) ISSN: 0008-5472 [Print] United States
• PMID: 1371092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antigens, CD7
• Antigens, Differentiation, T-Lymphocyte
• Immunotoxins
• Neoplasm Proteins
• Protein Synthesis Inhibitors
• Ricin

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antigens, CD (immunology)
• Antigens, CD7
• Antigens, Differentiation, T-Lymphocyte (immunology)
• Drug Screening Assays, Antitumor
• Glycosylation
• Humans
• Immunotoxins (chemistry, therapeutic use)
• Leukemia-Lymphoma, Adult T-Cell (metabolism, pathology, therapy)
• Mice
• Mice, SCID
• Neoplasm Proteins (biosynthesis)
• Neoplasm Transplantation
• Protein Synthesis Inhibitors (pharmacology)
• Ricin (chemistry, therapeutic use)
• Specific Pathogen-Free Organisms
• Tumor Cells, Cultured