Article: article from journal or magazin.
Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice
Journal of Clinical Investigation
Invariant NKT (iNKT) cells are potent activators of DCs, NK cells, and T cells, and their antitumor activity has been well demonstrated. A single injection of the high-affinity CD1d ligand alpha-galactosylceramide (alphaGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when alphaGalCer was loaded on a recombinant soluble CD1d molecule (alphaGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-gamma secretion as well as DC maturation in mice. Most importantly, when alphaGalCer/sCD1d was fused to a HER2-specific scFv antibody fragment, potent inhibition of experimental lung metastasis and established s.c. tumors was obtained when systemic treatment was started 2-7 days after the injection of HER2-expressing B16 melanoma cells. In contrast, administration of free alphaGalCer at this time had no effect. The antitumor activity of the CD1d-anti-HER2 fusion protein was associated with HER2-specific tumor localization and accumulation of iNKT, NK, and T cells at the tumor site. Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy
Animals , antagonists & inhibitors , Antibodies , Antigens,CD1 , Antigens,CD1d , Antineoplastic Agents , Biochemistry , biosynthesis , Cytotoxicity,Immunologic , Dendritic Cells , drug therapy , Female , Galactosylceramides , Immunoglobulin Fragments , immunology , Immunotherapy , Interferon-gamma , Killer Cells,Natural , Lung , Lung Neoplasms , Lymphocyte Activation , Melanoma , Melanoma,Experimental , Mice , Mice,Inbred C57BL , pathology , pharmacology , prevention & control , Proteins , Receptor,erbB-2 , Recombinant Fusion Proteins , secondary , secretion , Switzerland , therapeutic use
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