Synthetic unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides are potent stimulators of antileukemia responses in naive and bone marrow transplant recipients

Immunostimulatory cytosine-phophate-guanosine (CpG)-containing motifs in ba cterial DNA are potent immune system activators. Depending on the bases fla nking the CpG motif and on the DNA backbone, CpG oligodeoxynucleotides (ODN s) can induce relatively more B-cell activation or relatively more natural killer (NK)cell activation. To evaluate their antitumor activities, an NK-o ptimized ODN (1585) and 2 B-cell-optimized ODNs (1826 and 2006) were compar ed for their ability to protect naive mice against a lethal acute myelogeno us leukemia (AML) challenge. CpG 2006, but not CpG 1585, administered 2 day s before the AML challenge, allowed mice to survive more than 100 times a l ethal tumor dose. Cell depletion studies showed that protection did not req uire T or B cells but depended on NK cells and also on an NK-independent me chanism. CpG 2006 protected against AML challenge in both syngeneic and all ogeneic bone marrow transplant (BMT) recipients at both early and late time points after transplantation. Although CpG 1585 had no protective effect o n its own, it showed a striking synergy with CpG 2006 to induce prolonged s urvival to AML challenge in allogeneic recipients of T-cell-depleted marrow grafts, exceeding the survival benefit of donor lymphocyte infusion (DLI). When combined with DLI, a synergistic effect was observed in recipients of CpG2006 or 2006 + 1585 with 88% of mice surviving long-term. These data ar e the first to indicate that the systemic administration of CpG ODNs is a p otent means of inducing therapeutic anti-AML innate immune responses in nai ve and BMT recipients.