title: Enhancement of the anti-melanoma response of Hu14.18K322A by αCD40 + CpG.
abstract: Targeted monoclonal antibodies (mAb) can be used therapeutically for tumors with identifiable antigens such as disialoganglioside GD2, expressed on neuroblastoma and melanoma tumors. Anti-GD2 mAbs (αGD2) can provide clinical benefit in patients with neuroblastoma. An important mechanism of mAb therapy is antibody-dependent cellular cytotoxicity (ADCC). Combinatorial therapeutic strategies can dramatically increase the anti-tumor response elicited by mAbs. We combined a novel αGD2 mAb, hu14.18K322A, with an immunostimulatory regimen of agonist CD40 mAb and class B CpG-ODN 1826 (CpG). Combination immunotherapy was more effective than the single therapeutic components in a syngeneic model of GD2-expressing B16 melanoma with minimal tumor burden. NK cell depletion in B6 mice showed that NK cells were required for the anti-tumor effect; however, anti-tumor responses were also observed in tumor-bearing SCID/beige mice. Thus, NK cell cytotoxicity did not appear to be essential. Peritoneal macrophages from anti-CD40 + CpG-treated mice inhibited tumor cells in vitro in an hu14.18K322A antibody-dependent manner. These data highlight the importance of myeloid cells as potential effectors in immunotherapy regimens utilizing tumor-specific mAb and suggest that further studies are needed to investigate the therapeutic potential of activated myeloid cells and their interaction with NK cells.
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. kalderson@wisc.edu
authors.forename: Kory L
authors.initials: KL
authors.lastname: Alderson
authors.forename: Mitchell
authors.initials: M
authors.lastname: Luangrath
authors.forename: Megan M
authors.initials: MM
authors.lastname: Elsenheimer
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology; D005732:Gangliosides / Q000276:immunology*; D007116:Immunization, Passive / Q000379:methods; 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; D022423:Myeloid Cells / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C423449:CpG ODN 1826; D005732:Gangliosides; D009838:Oligodeoxyribonucleotides; C019403:ganglioside, GD2