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      1. Author :
        Bruyn, M. de; Wei, Y.; Wiersma, V. R.; Samplonius, D. F.; Klip, H. G.; Zee, A. G. van der; Yang, B.; Helfrich, W.; Bremer, E.
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        Journal Article
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      5. Publication :
        Clinical cancer research : an official journal of the American Association for Cancer Research
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      12. Abstract :
        PURPOSE: Adoptive T-cell therapy generally fails to induce meaningful anti-cancer responses in patients with solid tumors. Here, we present a novel strategy designed to selectively enhance the tumoricidal activity of T-cells by targeted delivery of TRAIL to the T-cell surface.EXPERIMENTAL DESIGN: We constructed two recombinant fusion proteins: anti-CD3:TRAIL and K12:TRAIL. Tumoricidal activity of T-cells in the presence of these fusion proteins was assessed in solid tumor cell lines, primary patient-derived malignant cells and in a murine xenograft model.RESULTS: When added to T-cells, K12:TRAIL and anti-CD3:TRAIL selectively bind to the T-cell surface antigens CD3 and CD7, respectively, leading to cell surface accretion of TRAIL. Subsequently, anti-CD3:TRAIL and K12:TRAIL increased the tumoricidal activity of T-cells towards cancer cell lines and primary patient-derived malignant cells greater than 500-fold. Furthermore, T-cell surface delivery of TRAIL strongly inhibited tumor growth and increased survival time of xenografted mice greater than 6-fold. CONCLUSIONS: Targeted delivery of TRAIL to cell surface antigens of T-cells potently enhances the tumoricidal activity of T-cells. This approach may be generally applicable to enhance the efficacy of adoptive T-cell therapy.
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