Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo.
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-gamma-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.
Biglari
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A
Cancer Research UK Gene Therapy Group and Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Southgate
T D
TD
Fairbairn
L J
LJ
Gilham
D E
DE
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D017452:Receptors, IgG / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous
D002272:Carcinoembryonic Antigen; D016207:Cytokines; D017452:Receptors, IgG; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins