Development of cellular cancer immunotherapy by using humaniPS-cell-derived dendritic cells and ideal cancer-associated antigens

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We established a method by which we can obtain a large number of functional dendritic cells (DC)with a simple procedure from human iPS cells. We transduced iPS cell-derived CD11b+myeloid cellswith cMYC and BMI1 genes associated with proliferative or anti-senescence effects. This made the cellscapable of propagating for more than 4 months in an M-CSF-dependent manner while retaining thecapacity to differentiate into DC. We named the iPS cell-derived proliferating myeloid cells “iPS-ML”,and the iPS-ML-derived dendritic cells “ML-DC”. In addition, we generated T AP2-deficient iPS cellclones by zinc finger nuclease-aided targeted gene disruption. T AP2-deficient iPS-ML avoidedrecognition by pre-activated allo-reactive CD8+T cells. The T AP2-deficient ML-DC expressingexogenously introduced HLA-A2 genes stimulated HLA-A2-restricted tumor antigen-specific CD8+Tcells obtained from HLA-A2-positive allogeneic donors, resulting in generation of tumorantigen-specific CTL lines. T AP-deficient iPS-ML introduced with various HLA class I genes may serveas an unlimited source of DC for vaccination therapy . Based on the present study , we propose aDC-producing system, which is simple, safe, and applicable to any patients irrespective of their HLAtypes. This technology will pave the way for the mass production of DC for therapeutic use. We havealso succeeded in inhibition of tumor growth of intraperitoneal dissemination of human cancer cells inimmune-deficient mice by intraperitoneal injection of human iPS-macrophage genetically modified tosecrete interferon-beta.