CpG-
oligodeoxynucleotides (
CpG-ODN) exhibit potent immunostimulatory activity by binding with
Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of
chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic
tumor xenograft.
Chemotherapy consisted of the maximum tolerated dose of
gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 microg/mouse), weekly, after the end of
chemotherapy. CpG-ODNs alone had little effect on
tumor growth, whereas
gemcitabine alone significantly delayed the median time of disease onset (palpable i.p.
tumor) and of bulky disease development (extensive peritoneal
tumor burden), but did not enhance survival time. When the
gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus
gemcitabine-treated mice). Autoptic examination showed that
tumor spread in the peritoneal cavity was reduced to a greater extent than with
gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the
tumor response. The clear improvement of survival observed in an orthotopic murine model of human
pancreatic cancer by the combined use of CpG-ODNs with
chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.