title: Enhanced T-cell-independent antitumor effect of cyclophosphamide combined with anti-CD40 mAb and CpG in mice.
abstract: We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.
authors.affiliation: Paul P. Carbone Comprehensive Cancer Center, Department of Surgery, University of Wisconsin, Madison, WI, USA.
authors.forename: Erik E
authors.initials: EE
authors.lastname: Johnson
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Buhtoiarov
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Baldeshwiler
authors.forename: Mildred A R
authors.initials: MA
authors.lastname: Felder
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D005434:Flow Cytometry; D007121:Immunocompetence; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D003520:Cyclophosphamide