In vivo anti-leukemic efficacy of anti-CD7-pokeweed antiviral protein immunotoxin against human T-lineage acute lymphoblastic leukemia/lymphoma in mice with severe combined immunodeficiency.
Mice with severe combined immunodeficiency (SCID) were injected with 1 x 10(7) MOLT-3 human T-lineage acute lymphoblastic leukemia cells to provide a model for the evaluation of anti-CD7-pokeweed antiviral protein (PAP) immunotoxin directed against the human CD7 antigen. Of control SCID mice (treated with phosphate-buffered saline, PBS) challenged intravenously with 1 x 10(7) MOLT-3 cells, 5/5 died at 29 to 35 days after inoculation, with a median event-free survival of 33 days. Similarly, 6/6 anti-CD19-PAP treated control SCID mice died of MOLT-3 leukemia at a median of 36 days. In contrast, treatment with anti-CD7-PAP (15 micrograms total dose in 5 micrograms intraperitoneal injections on days 1-3) significantly improved event-free survival of SCID mice challenged with 1 x 10(7) MOLT-3 cells. Of nine SCID mice treated with anti-CD7-PAP, four died at 54-149 days and five remained alive for > 172 days without clinical evidence of leukemia (median event-free survival > 172 days). When long-term survivors among the anti-CD7-PAP treated SCID mice were electively killed at 173 days to assess their leukemia burden, histopathologic examination and polymerase chain reaction provided evidence of disseminated leukemia in some of these mice. Intriguingly, marked differences in morphology, tissue distribution, and histologic pattern of organ invasion existed between leukemic blasts killing 100% of PBS-treated control mice at a median of 33 days and 'therapy-refractory' leukemic blasts detected in anti-CD7-PAP-treated long-term survivors. This novel SCID mouse model of disseminated human T-lineage ALL provides a unique in vivo system to investigate the therapeutic potential of new treatment strategies and to study possible mechanisms of in vivo immunotoxin resistance.
Gunther
R
R
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Health Sciences Center, Minneapolis.
Chelstrom
L M
LM
Finnegan
D
D
Tuel-Ahlgren
L
L
Irvin
J D
JD
Myers
D E
DE
Uckun
F M
FM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001483:Base Sequence; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D017254:Leukemic Infiltration; D008223:Lymphoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases; D009368:Neoplasm Transplantation; D015345:Oligonucleotide Probes; D010940:Plant Proteins / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy*; D054789:Ribosome Inactivating Proteins, Type 1; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D015345:Oligonucleotide Probes; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein