Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide.
Human mixed lineage leukemia cell line RS4;11 with the t(4;11)(q21;q23) translocation causes disseminated and invariably fatal leukemia in mice with severe combined immunodeficiency. Whereas an immunotoxin constructed from the murine anti-CD19(B43) monoclonal antibody and the plant toxin pokeweed antiviral protein (B43-PAP) has a potent in vitro anti-leukemic effect against clonogenic RS4;11 cells, its activity is further potentiated by the active cyclophosphamide congener mafosfamid. These intriguing observations prompted us to evaluate the in vivo antileukemic efficacy of combined immunochemotherapy employing B43-PAP immunotoxin plus cyclophosphamide against human t(4;11) leukemia cells in an RS4;11 severe combined immunodeficiency (SCID) mouse model system. Intravenous injections of B43-PAP or cyclophosphamide improved survival of SCID mice challenged with RS4;11 leukemia, as reflected by markedly prolonged median survival times. After intravenous inoculation of 5 x 10(7) RS4;11 leukemia cells, the median survival times were 41 days for saline-treated control mice (n = 12), 44 days for control mice treated with unconjugated B43 monoclonal antibody and PAP (n = 12), 56 days for mice treated with the control immunotoxin G17.2 (anti-CD4)-PAP (n = 6), 79 days for B43-PAP-treated test mice (n = 12), and 80 days for cyclophosphamide-treated test mice (n = 16). Notably, combined immunochemotherapy using B43-PAP plus cyclophosphamide was significantly more effective than either B43-PAP or cyclophosphamide alone. The median survival time for a total of 22 SCID mice undergoing combined immunochemotherapy with B43-PAP followed by cyclophosphamide (n = 12) or cyclophosphamide followed B43-PAP (n = 10) was > 150 days. The Kaplan-Meier estimates and standard errors of the probability of event-free survival at 5 months after inoculation of 5 x 10(7) RS4;11 cells were 21 +/- 13% for B43-PAP-treated mice, 7 +/- 6% for cyclophosphamide-treated mice, 90 +/- 10% for mice treated with B43-PAP followed by cyclophosphamide (n = 12), and 90 +/- 10% for mice treated with cyclophosphamide followed by B43-PAP (n = 10). Our results lead us to recommend that initial consideration be given to combined immunochemotherapy protocols using B43-PAP immunotoxin plus cyclophosphamide for treatment of refractory or relapsed t(4;11) leukemias.
Jansen
B
B
Bone Marrow Transplantation Program, University of Minnesota, Minneapolis 55455.
Kersey
J H
JH
Jaszcz
W B
WB
Gunther
R
R
Nguyen
D P
DP
Chelstrom
L M
LM
Tuel-Ahlgren
L
L
Uckun
F M
FM
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D017254:Leukemic Infiltration; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases; D015345:Oligonucleotide Probes; D010940:Plant Proteins / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D054789:Ribosome Inactivating Proteins, Type 1; D013047:Specific Pathogen-Free Organisms; D014178:Translocation, Genetic
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D015345:Oligonucleotide Probes; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C048341:mafosfamide; D003520:Cyclophosphamide; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein