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  • Book
    Mark Ping Chao.
    Digital2010
    Growing evidence indicates that cancers are composed of functionally heterogeneous cells that are organized by a cellular hierarchy and are maintained by a stem cell-like population. Given their unique ability to initiate tumor growth, eradication of these cancer stem cells (CSC) is necessary for cure. Thus, the development of CSC targeted therapies is necessary to improve current clinical outcomes. This body of work identifies CD47 as a therapeutic target on CSC and bulk cells in several human malignancies. CD47 is a cell surface protein that functions to inhibit phagocytosis through binding its ligand SIRP[Alpha], expressed on phagocytes. Compared to normal cell counterparts, CD47 was highly expressed on several human tumors including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL), suggesting that higher CD47 levels on tumors allow evasion of immune phagocytosis. Higher CD47 expression in these tumors correlated with a worse clinical prognosis and was an independent prognostic factor. Furthermore, a monoclonal blocking antibody against CD47 enabled phagocytosis of human AML, ALL, and NHL in vitro and eliminated disease in vivo. When combined with the Fc receptor-activating antibody, rituximab, anti-CD47 antibody therapy achieved high cure rates in pre-clinical models of NHL in contrast to partial responses with either agent alone. Lastly, anti-CD47 antibody treatment specifically targeted tumor but not normal cells, resulting in minimal toxicity in vitro and in vivo. The selective targeting of tumor cells by anti-CD47 antibody was due to the selective expression of the pro-phagocytic signal, calreticulin on tumor but not normal cells. In summary, this body of work identifies CD47 as a therapeutic target on several human cancers and that a monoclonal blocking antibody against CD47 has pre-clinical efficacy in eliminating these tumors through the promotion of phagocytosis.