CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma

Purpose: CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences that mimic bacterial DNA and have potent immunostimulatory effects on dendritic cells (DCs), B cells, and natural killer cells. To evaluate CpG ODN antitumor effects against solid tumors, we used an orthotopic murine model of embryonal rhabdomyosarcoma. Experimental Design: The systemic administration of CpG 2006 was tested beginning on day 9 or 19 when tumors were not yet palpable or palpable, respectively, and after surgical resection of the tumor. CpG was also administered in combination with the chemotherapeutic agents, cyclophosphamide (CY) and topotecan, or surgical resection. Results: Systemic CpG prolonged survival when begun at day 9 but had no effect with a large tumor burden. CpG administered after surgical resection of tumor significantly improved survival of mice (P < 0.03). On day 9, CY plus CpG 2006 resulted in improved survival compared with CY alone (70% versus 41%, respectively). Survival was significantly improved when CpG 2006 was administered systemically with CY beginning on day 19 (15% versus 0% survival). The administration of CpG 2006 with topotecan significantly improved survival in mice with large tumors. Cell-depletion studies demonstrated that the antitumor effects of systemically administered CpG 2006 combined with CY were predominantly T cell dependent. Conclusions: These data are the first to show that immune stimulatory agents such as CpGs may enhance the antitumor effects of chemotherapeutic agents and improve survival after surgical resection of a solid tumor.