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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2008-2013.
Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-02-002055.
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Submitted February 6, 2006
Accepted October 17, 2006
In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides
Hisaki Fujii, Jacqueline D Trudeau, David Teachey, Jonathan D Fish, Stephan A Grupp, Kirk R Schultz, and Gregor SD Reid*
Division of Hematology/Oncology/Bone Marrow Transplantation, BC Children's Hospital, Vancouver, Canada
Dept of Oncology, Children's Hospital of Philadelphia, PA
* Corresponding author; email: reidg{at}email.chop.edu.
Despite considerable success in treating newly diagnosed childhood acute lymphoblastic leukemia (ALL), relapsed disease remains a significant clinical challenge. Using a NOD/SCID mouse xenograft model, we report that immunostimulatory DNA oligonucleotides containing CpG motifs (CpG ODN) stimulate significant immune activity against primary human ALL cells in vivo. The administration of CpG ODN induced a significant reduction in systemic leukemia burden, mediated continued disease control, and significantly improved survival of mice with established human ALL. The death of leukemia cells in vivo was independent of the ability of ALL cells to respond directly to CpG ODN, and correlated with the production of IL-12p70, IFN- and IFN- by the host. In addition, depletion of natural killer cells by anti asialo-GM1 treatment significantly reduced the in vivo anti-leukemic activity of CpG ODN. This anti-leukemia effect was not limited to the xenograft model, as natural killer cell-dependent killing of ALL by human PBMC was also increased by CpG ODN stimulation. These results suggest that CpG ODN have potential as therapeutic agents for the treatment of ALL.
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