Generation of long-term protection from acute lymphoblastic leukemia (ALL) by an immune stimulant in a syngeneic murine model (41.21)

Abstract

Abstract ALL is the most common childhood cancer, and relapsed ALL remains a major cause of mortality. The success of stem cell transplant for relapsed ALL suggests immune therapy may be effective. We previously showed CpG ODN, which stimulate immune activity through TLR9, enhance allogeneic Th1 responses and reduce in vivo leukemic burden of primary human ALL xenografts. We are now evaluating anti-leukemia activity induced by CpG ODN in a pre-B ALL minimal residual disease (MRD) model. In mice given 106 syngeneic lymphoblasts, CpG ODN treatment universally induced remissions for >6 months; control mice died of leukemia at a median of 35 days (p=0.0001). CpG ODN treatment of Rag-1-deficient mice significantly decreased peripheral disease at day 28 (p<0.05) but did not induce long-term remissions (p<0.01). T cell-depletion after CpG ODN similarly abrogated protection from ALL, resulting in a median survival of 39 days (p<0.0001). Mice in remission after CpG ODN were protected from rechallenge with ALL blasts, while age-matched leukemia-naïve controls rapidly died of disease (p=0.0005). A protective effect is also noted in mice treated with CpG ODN versus PBS following standard ALL chemotherapy (p<0.03). To our knowledge, this is the first demonstration that CpG ODN induce a durable remission in an ALL MRD model by triggering an adaptive immune response, suggesting this treatment may have clinical utility in children with MRD.