title: CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model.
abstract: Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor-associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models.
authors.affiliation: Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Jordan
authors.affiliation: Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA. Electronic address: djw@bu.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Waxman
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D009841:Oligonucleotides / Q000008:administration & dosage*; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D003520:Cyclophosphamide
keywords: Chemoimmunotherapy; CpG oligodeoxynucleotide; Glioma; Metronomic cyclophosphamide