Submitted February 9, 2006
Accepted July 22, 2006
Continuous delivery of human type I interferons (
/
) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model
Reuben Benjamin, Asim Khwaja, Nalini Singh, Jenny McIntosh, Anthony Meager, Meenu Wadhwa, Christian Streck, Catherine Ng, Andrew M Davidoff, and Amit C Nathwani*
Department of Haematology, University College London, United Kingdom
Division of Immunology & Endocrinology, National Institute for Biological Standards & Control, United Kingdom
Division of Experimental Hematology & Dept of Surgery, St Jude Children's Research Hospital, Memphis, TN, United States
National Blood Service, United Kingdom
* Corresponding author; email: a.nathwani{at}ucl.ac.uk.
In this study we focused primarily on the antileukemic activity of interferon-
(IFN-) in a murine xenograft model of acute myeloid leukemia (AML). Bolus administration of recombinant IFN- via the subcutaneous or intravenous route failed to show efficacy in mice injected with AML cells despite achieving peak plasma IFN- levels of >200 IU/ml. In contrast, stable expression of IFN- following adeno-associated virus vector (AAV) mediated gene transfer resulted in significant antileukemic activity against primary AML cells derived from patients with poor prognostic markers. An almost linear relationship was observed with stable plasma levels of IFN- and antileukemic activity in mice. Even levels less than 10 IU/ml were able to reduce tumor load by 50 fold when compared to control animals. These levels of IFN- are likely to be non-toxic in humans. Therefore approaches capable of maintaining stable plasma levels of IFN- merit further clinical evaluation in patients with AML.
