Cancer Immunology, Immunotherapy

, Volume 62, Issue 4, pp 665–675 | Cite as

Enhancement of the anti-melanoma response of Hu14.18K322A by αCD40 + CpG

  • Kory L. Alderson
  • Mitchell Luangrath
  • Megan M. Elsenheimer
  • Stephen D. Gillies
  • Fariba Navid
  • Alexander L. Rakhmilevich
  • Paul M. Sondel
Original article

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.

Keywords

GD2 Melanoma Antibody-dependent cellular cytotoxicity (ADCC) CD40 Macrophage NK cell 

Notes

Acknowledgments

This work was supported by National Institutes of Health Grants CA032685, CA87025, CA166105, CA14520, GM067386, Department of Defense grant W81XWH-08-1-0559 and grants from the Midwest Athletes for Childhood Cancer Fund, the Crawdaddy Foundation and The Evan Dunbar Foundation.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Kory L. Alderson
    • 1
  • Mitchell Luangrath
    • 1
  • Megan M. Elsenheimer
    • 1
  • Stephen D. Gillies
    • 2
  • Fariba Navid
    • 3
  • Alexander L. Rakhmilevich
    • 1
    • 4
  • Paul M. Sondel
    • 1
    • 4
    • 5
  1. 1.Department of Human OncologyUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Provenance Biopharmaceuticals Corp.BurlingtonUSA
  3. 3.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Paul Carbone Comprehensive Cancer CenterUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.Department of PediatricsUniversity of Wisconsin-MadisonMadisonUSA

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