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Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

Cancer Gene Therapy volume 16, pages 900–911 (2009)Cite this article

Abstract

A number of monoclonal antibodies (mAbs) have been studied for their ability to enhance immune responses. Although these antibodies are effective in pre-clinical and clinical studies, they are costly and have occasionally been associated with adverse effects such as autoimmunity and cytokine storm. Numerous studies have shown that treatment of mice with an agonistic mAb, clone DTA-1, targeting murine glucocorticoid-induced tumor necrosis factor receptor (GITR) results in enhanced immune responses in tumor-bearing animals. Herein, we evaluate the novel approach of transfecting dendritic cell (DC) with mRNA encoding the heavy and light chain of the anti-GITR mAb. We show the induction of significantly enhanced tumor immunity by vaccinating with a combination of anti-GITR-secreting DC and tumor antigen-presenting DC. This enhancement is comparable to that seen with systemically delivered mAb along with the antigen-presenting DC. Importantly, when anti-GITR was delivered using RNA-transfected DC, we observed no evidence of autoimmune hypopigmentation in any tumor-free mice. We also show enhanced induction of cytotoxic T-lymphocyte responses, which is only observed when the antigen-presenting and antibody-secreting DC are co-injected at the same site. To illustrate the broad utility of this strategy, we show that DC transfected with mRNA encoding GITR-ligand/Fc fusion protein is also an effective tumor vaccine adjuvant.

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Abbreviations

DC:

dendritic cells

GITR:

glucocorticoid-induced TNF receptor

H+L:

heavy and light

LN:

lymph node

mAb:

monoclonal antibody

OVA:

chicken ovalbumin

Treg:

regulatory T cell

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Acknowledgements

We thank David Snyder for assistance with animal studies. We are grateful to Dr Eli Gilboa (University of Miami, Miami, FL) and Dr Bruce Sullenger (Duke University, Durham, NC) for helpful comments and Dr Shimon Sakaguchi (Kyoto University, Japan) for providing us with the DTA-1 anti-GITR hybridoma.

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    D Boczkowski, J Lee & S Nair

  2. Surgical Services, Durham Veterans Administration Medical Center, Durham, NC, USA

    S Pruitt

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  1. D Boczkowski
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Correspondence to S Nair.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)

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Boczkowski, D., Lee, J., Pruitt, S. et al. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Ther 16, 900–911 (2009). https://doi.org/10.1038/cgt.2009.39

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