Source Paper
Stephen B. Willingham, Jens-Peter Volkmer, Andrew J. Gentles, Debashis Sahoo, Piero Dalerba et al.
Proceedings of the National Academy of Sciences • 2012
CD47, a “don't eat me” signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
Objective: To assess the effects of anti-CD47 antibody therapy on tumor growth and mouse survival in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells
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Establish orthotopic immunodeficient mouse xenotransplantation models using patient tumor cells
Note: Models were established with patient tumor cells in immunodeficient mice
“Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells”
Administer anti-CD47 antibodies to mice with established tumors to inhibit tumor growth and increase survival
Note: Therapy can be initiated on larger tumors to inhibit growth and prevent/treat metastasis, or on smaller tumors for potential curative effect
“Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative”
Track tumor growth and survival outcomes in mice receiving anti-CD47 antibody therapy over time
Note: Survival was increased in treated mice over time
“Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time”
Test safety and efficacy of targeting CD47 in immune competent hosts using an orthotopic mouse breast cancer model
Note: Further validation of CD47 targeting was performed in immune competent animals
“The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model”
Immunodeficient mice used for xenotransplantation models; also immune competent hosts used for orthotopic mouse breast cancer model validation