Ten thousand people in the U.S. develop acute myeloid leukemia (AML) each year. While many patients achieve remissions with combination chemotherapy, most relapse and die with drug resistant disease. We have produced a diphtheria fusion protein (DT388GMCSF) consisting of the catalytic and translocation domains of diphtheria toxin fused to human granulocyte-macrophage colony- stimulating factor. We initiated a phase I single-arm, inter-patient dose escalation clinical trial of five daily intravenous infusions for patients with relapsed or refractory AML. To date, we have observed dose- related transient elevations in liver enzymes and circulating inflammatory cytokines. Half of the patients were found to have pre- treatment antibodies to DT388GMCSF >2mu g/mL associated with reductions in the peak blood concentrations of DT388GMCSF. Clinical remissions have been observed at the higher dose levels. In the next funding period, we propose to better define the potential role for DT388GMCSF in the care of AML patients. We will complete the on- going phase I study and expand the cohort of patients at the maximal tolerated dose to better estimate the preliminary response rate and side effects. Further, we propose three areas of laboratory studies to be carried out to facilitate our understanding of the molecular pharmacology of DT388GMCSF in these patients.
In Specific Aim 1, the molecular mechanism for the liver damage and cytokine release will be investigated. The amount and types of cytokines released into the blood will be measured. Patient cytokine gene polymorphisms will be determined. A rat model will be used to determine whether the cytokines induce the liver injury. Methods of prevention of the cytokine release and liver injury in the rat will be tested. If successful, such measures may be tested in patients.
In Specific Aim 2, anti- DT388GMCSF antibody formation and DT388GMCSF serum levels will continue to be measured and correlated with toxicity and response.
In Specific Aim 3, pre-treatment blast proliferation sensitivity to DT388GMCSF will be measured and correlated with clinical response. These studies should lead to the design of pivotal phase II clinical trials to determine the role of this therapeutic in AML management.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CONC (01))
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Wu, Roy S
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Scott and White Memorial Hospital
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Frankel, Arthur; Liu, Jen-Sing; Rizzieri, David et al. (2008) Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. Leuk Lymphoma 49:543-53
Watson, Linley E; Mock, Jonathan; Lal, Hind et al. (2007) Lethal and edema toxins of anthrax induce distinct hemodynamic dysfunction. Front Biosci 12:4670-5
Thorburn, Andrew; Frankel, Arthur E (2006) Apoptosis and anthracycline cardiotoxicity. Mol Cancer Ther 5:197-9
Hogge, Donna E; Yalcintepe, Leman; Wong, Siaw-Hui et al. (2006) Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors. Clin Cancer Res 12:1284-91
Liu, Tie Fu; Hall, Philip D; Cohen, Kimberley A et al. (2005) Interstitial diphtheria toxin-epidermal growth factor fusion protein therapy produces regressions of subcutaneous human glioblastoma multiforme tumors in athymic nude mice. Clin Cancer Res 11:329-34
Testa, Ugo; Riccioni, Roberta; Biffoni, Mauro et al. (2005) Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression. Blood 106:2527-9
Cohen, Kimberley A; Liu, Tie Fu; Cline, J Mark et al. (2005) Safety evaluation of DT388IL3, a diphtheria toxin/interleukin 3 fusion protein, in the cynomolgus monkey. Cancer Immunol Immunother 54:799-806
Urieto, Jeffrey O; Liu, TieFu; Black, Jennifer H et al. (2004) Expression and purification of the recombinant diphtheria fusion toxin DT388IL3 for phase I clinical trials. Protein Expr Purif 33:123-33
Westcott, Marlena M; Abi-Habib, Ralph J; Cohen, Kimberley A et al. (2004) Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. Mol Cancer Ther 3:1681-9
Cohen, Kimberley A; Liu, Tie Fu; Cline, J Mark et al. (2004) Toxicology and pharmacokinetics of DT388IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human interleukin 3 (IL3), in cynomolgus monkeys. Leuk Lymphoma 45:1647-56

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