Anti-CD47 targeting therapy for the treatment of colon and pancreas cancers.

Abstract

CD47 is a “don’t eat me” signal over expressed on cancer cells inhibiting their engulfment by phagocytes. A novel monoclonal antibody, Hu5F9-G4, blocking CD47’s interaction with its ligand SIRPα allowed for phagocytosis of colorectal and pancreas tumors by macrophages. In some models, treatment of xenotransplanted tumors in immunodeficient mice with anti-CD47 antibodies strongly reduced tumor growth. In other models, the combination of anti-CD47 and anti-EGFR antibodies regressed tumor burden, where neither single agent therapy was as effective. Even in KRAS mutated tumors, where use of anti-EGFR antibodies is not indicated, the combination of antibodies lead to major tumor reduction. Taken collectively, Hu5F9-G4 is an effective treatment in colorectal and pancreas cancers, and in the combination of Hu5F9-G4 with an anti-EGFR antibody is therapeutically effective in KRAS mutated tumors in mouse xenografts. Cancer immunotherapy, including anti-CD47 blockade, tries to utilize the host’s own immune system to mount an immune response to cancer. To date, there have been a multitude of new therapies from cytokine treatments, to cell based vaccines, to antibody therapies which all recruit immune cells that have been somehow silenced by the tumor microenvironment. The Weissman lab’s own studies into the adaptive immune system suggest that upon phagocytosis, mediated by anti-CD47 antibodies, the subsequent T cell presentation preferentially recruits cytotoxic T cells. Here, we propose two additional model systems to further investigate the role CD47 plays in antigen presentation and downstream T cell recruitment to target cancer cells. Recent advances with immunotherapy agents for the treatment of cancer has provided remarkable, and in some cases, curative results. Blockade of the CD47:SIRPα axis between tumor cells and innate immune cells increases tumor cell phagocytosis in both solid tumors and hematological malignancies. These phagocytic innate cells are also professional antigen presenting cells, providing a link from innate to adaptive anti-tumor immunity. Preliminary studies have demonstrated that APCs present antigens from phagocytosed tumor cells, causing T cell activation. Therefore, agents that block CD47:SIRP-α engagement are attractive therapeutic targets as a monotherapy or in combination with additional immune modulating agents for activating anti-tumor T cells in vivo.