Abstract
We have evaluated the carbohydrate antigen LewisY (LeY) as a potential target for T-cell immunotherapy of hematological neoplasias. Analysis of 81 primary bone marrow samples revealed moderate LeY expression on plasma cells of myeloma patients and myeloblasts of patients with acute myeloid leukemia (AML) (52 and 46% of cases, respectively). We developed a retroviral vector construct encoding a chimeric T-cell receptor that recognizes the LeY antigen in a major histocompatibility complex-independent manner and delivers co-stimulatory signals to achieve T-cell activation. We have shown efficient transduction of peripheral blood-derived T cells with this construct, resulting in antigen-restricted interferon-γ secretion and cell lysis of LeY-expressing tumor cells. In vivo activity of gene-modified T cells was demonstrated in the delayed growth of myeloma xenografts in NOD/SCID mice, which prolonged survival. Therefore, targeting LeY-positive malignant cells with T cells expressing a chimeric receptor recognizing LeY was effective both in vitro and in a myeloma mouse model. Consequently, we plan to use T cells manufactured under Good Manufacturing Practice conditions in a phase I immunotherapy study for patients with LeY-positive myeloma or AML.
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Acknowledgements
This study was supported in part by the Translational Research Grant 6073-06 from the Leukemia and Lymphoma Society USA and by the Leukaemia Foundation of Victoria, Australia and a philanthropic fund from C & M Morris, Albert Park, Victoria, Australia.
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Peinert, S., Prince, H., Guru, P. et al. Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen. Gene Ther 17, 678–686 (2010). https://doi.org/10.1038/gt.2010.21
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DOI: https://doi.org/10.1038/gt.2010.21
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