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

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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.

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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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Authors and Affiliations

  1. Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA

    Kory L. Alderson, Mitchell Luangrath, Megan M. Elsenheimer, Alexander L. Rakhmilevich & Paul M. Sondel

  2. Provenance Biopharmaceuticals Corp., Burlington, MA, USA

    Stephen D. Gillies

  3. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Fariba Navid

  4. Paul Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, USA

    Alexander L. Rakhmilevich & Paul M. Sondel

  5. Department of Pediatrics, University of Wisconsin-Madison, 1111 Highland Ave- WIMR 4156, Madison, WI, 53705, USA

    Paul M. Sondel

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  1. Kory L. Alderson
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Correspondence to Kory L. Alderson.

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Alderson, K.L., Luangrath, M., Elsenheimer, M.M. et al. Enhancement of the anti-melanoma response of Hu14.18K322A by αCD40 + CpG. Cancer Immunol Immunother 62, 665–675 (2013). https://doi.org/10.1007/s00262-012-1372-8

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