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 Blood, 17 September 2009, Vol. 114, No. 12, pp. 2459-2466.
Prepublished online as a Blood First Edition Paper on July 27, 2009; DOI 10.1182/blood-2009-02-203984.

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LYMPHOID NEOPLASIA

Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses

Alix E. Seif1, David M. Barrett1, Michael Milone2, Valerie I. Brown1,3, Stephan A. Grupp1,3, and Gregor S. D. Reid1

1 Division of Oncology, Children's Hospital of Philadelphia, PA; and 2 Department of Pathology and Laboratory Medicine and 3 School of Medicine, University of Pennsylvania, Philadelphia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a major cause of mortality in children with recurrent disease and in adults. Despite observed graft-versus-leukemia effects after stem cell transplantation, successful immune therapies for ALL have proven elusive. We previously reported immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG ODN) enhance allogeneic Th1 responses and reduce leukemic burden of primary human ALL xenografts. To further the development of CpG ODN as a novel ALL therapy, we investigated the antileukemia activity induced by CpG ODN in a transplantable syngeneic pre-B ALL model. CpG ODN induced early killing of leukemia by innate immune effectors both in vitro and in vivo. Mice were treated with CpG ODN starting 7 days after injection with leukemia to mimic a minimal residual disease state and achieved T cell–dependent remissions of more than 6 months. In addition, mice in remission after CpG ODN treatment were protected from leukemia rechallenge, and adoptive transfer of T cells from mice in remission conferred protection against leukemia growth. To our knowledge, this is the first demonstration that CpG ODN induce a durable remission and ongoing immune-mediated protection in ALL, suggesting this treatment may have clinical utility in patients with minimal residual disease.


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