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 evalu ate new approaches for the treatment of acute myeloid leukemia (AML). We ha ve previously demonstrated the killing of SCID mouse leukemia initiating ce lls 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 DI-huGM-CSF eliminates AML growth in SCID mice. Seven cases of AML were studied. SCID m ice were treated intraperitoneally with the maximally tolerated dose of 75 mu g/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 c hain reaction (STR-PCR) analysis. Four out of seven AML cases were sensitiv e 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 c ytometry 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-huG M-CSF. Sensitivity was correlated with GM-CSFR expression. Our data show th at DT-huGM-CSF can be used in vivo to reduce growth of AML and warrant furt her development of DT-I huGM-CSF for the treatment of human AML.