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Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo

Gene Therapy volume 13, pages 602–610 (2006)Cite this article

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is one means by which macrophages (as well as natural killer cells and granulocytes) elicit a cytotoxic response. This is achieved via interaction of the Fc-γ-receptor (CD64) with the Fc portion of antibody bound to target cells. We have created a chimeric CD64 molecule that incorporates a single chain Fv molecule, targeted against human carcinoembryonic antigen (CEA), fused to the membrane spanning and cytosolic domains of human CD64. Following adenoviral transfer to primary human monocytes, this chimeric CD64 receptor induced antigen-specific cytokine secretion during culture on immobilised CEA protein or on CEA-expressing tumour cells. Moreover, CEA targeted, but not control, monocytes effectively retarded CEA-positive tumour cell growth in vitro. Importantly, targeted monocyte cultures significantly reduced in vivo tumour growth rates in xenograft studies resulting in improved survival rates over that of control monocyte cultures. These data suggest that genetically directing monocytes against tumour antigens may be a useful means of achieving an immunotherapeutic response.

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Acknowledgements

We thank Professor Robert Hawkins (Medical Oncology, Paterson Institute for Cancer Research, [PICR]) for advice and support and Lorna B Woolford (Cancer Reseach UK Gene Therapy Unit, PICR) for technical assistance. The PICR molecular biology, FACs and BRU core facilities provided invaluable help. This work was supported by Christie Hospital NHS Endowments (AB) and Cancer Research UK (TS, LF, DG).

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Author notes

  1. A Biglari

    Present address: Department of Pathology, School of Medicine Zanjan University of Medical Sciences, Zanjan, Iran

  2. L J Fairbairn: Deceased.

Authors and Affiliations

  1. Cancer Research UK Gene Therapy Group and Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK

    A Biglari, T D Southgate, L J Fairbairn & D E Gilham

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  2. T D Southgate
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Correspondence to D E Gilham.

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

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Biglari, A., Southgate, T., Fairbairn, L. et al. Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo. Gene Ther 13, 602–610 (2006). https://doi.org/10.1038/sj.gt.3302706

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