GM-CSF receptor targeted treatment of primary AML in SCID mice using Diphtheria toxin fused to huGM-CSF.
The severe combined immunodeficient (SCID) mouse model may be used to evaluate new approaches for the treatment of acute myeloid leukemia (AML). We have previously demonstrated the killing of SCID mouse leukemia initiating cells by in vitro incubation with human GM-CSF fused to Diphtheria toxin (DT-huGM-CSF). In this report, we show that in vivo treatment with DT-huGM-CSF eliminates AML growth in SCID mice. Seven cases of AML were studied. SCID mice were treated intraperitoneally with the maximally tolerated dose of 75 microg/kg/day for 7 days. Antileukemic efficacy was determined at days 40 and 80 after transplantation, by enumerating the percentages of human cells in SCID bone marrow using flow cytometry and short tandem repeat polymerase chain reaction (STR-PCR) analysis. Four out of seven AML cases were sensitive to in vivo treatment with DT-huGM-CSF at both evaluation time points. In three of these cases, elimination of human cells was demonstrated by flow cytometry and STR-PCR. One AML case showed moderate sensitivity for DT-huGM-CSF, and growth of the two remaining AML cases was not influenced by DT-huGM-CSF. Sensitivity was correlated with GM-CSFR expression. Our data show that DT-huGM-CSF can be used in vivo to reduce growth of AML and warrant further development of DT-huGM-CSF for the treatment of human AML.
Rozemuller
H
H
Institute of Hematology, Erasmus University, Rotterdam, The Netherlands.
Terpstra
W
W
Rombouts
E J
EJ
Lawler
M
M
Byrne
C
C
FitzGerald
D J
DJ
Kreitman
R J
RJ
Wielenga
J J
JJ
Löwenberg
B
B
Touw
I P
IP
Hagenbeek
A
A
Martens
A C
AC
D000818:Animals; D001853:Bone Marrow; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D013047:Specific Pathogen-Free Organisms
D004273:DNA, Neoplasm; D004167:Diphtheria Toxin; D000922:Immunotoxins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor