Metronomic chemotherapy, in which cytotoxic drugs are delivered at low doses at regular, intermittent intervals, has shown promising clinical results in several cancers and offers the benefit of reduced patient toxicity compared to conventional maximum tolerated dose chemotherapy. We previously showed that cyclophosphamide (CPA) treatment on a 6-day repeating metronomic schedule regresses implanted gliomas by an immune-mediated mechanism. Here, we examine whether this immune-stimulatory metronomic chemotherapy can be enhanced by combination with TLR9-stimulating CpG-1826 immunotherapy in GL261 gliomas implanted in immunocompetent BL6 mice. CpG-1826 treatment activated an anti-tumor immune response in ~50% of mice, associated with a strong increase in tumor-associated macrophages. CpG-1826 was ineffective against GL261 tumors implanted in T cell- and B cell-deficient scid mice, suggesting that adaptive immunity is essential. Combination of CpG-1826 with metronomic CPA sensitized GL261 gliomas in both CpG-1826-responsive and CpG-1826-non-responsive mice, increasing infiltration of tumor-associated macrophages, dendritic cells, and T cells and increasing anti-tumor activity. Further, the combination treatment elicited long-term regression and immune memory in a subset of glioma-bearing mice. To identify potential mechanisms for this enhanced response to the combination therapy, we assayed a number of immune-related genes in the treated tumors, including feedback inhibitory immunosuppressive T cell factors that are induced by metronomic CPA treatment. Combination of CpG-1826 with metronomic CPA failed to induce several of these factors, suggesting that TLR9-based immunotherapy can enhance the anti-tumor activity of metronomic CPA by interdicting feedback immune inhibition mechanisms. Grant support: CA49248 (to DJW).
Citation Format: Marie Jordan, David J. Waxman. Low dose, metronomic cyclophosphamide therapy sensitizes tumors to CpG-1826 immunotherapy in a preclinical glioma model. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B121.
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