Cc-90002 (Anti-Cd47 Antibody) In Vivo Anti-Tumor Activity Is Associated With An Increase In M1-Polarized Macrophages

CD47, also known as integrin-associated protein, is over-expressed in several tumor types, including AML, NHL, breast cancer and multiple myeloma. Elevated expression of CD47 on the cell surface protects tumors from phagocytosis by macrophages through binding to signal regulatory protein alpha (SIRPα) on the surface of macrophages. The CD47-SIRPα interaction triggers events that culminate in the inhibition of the phagocytic process. Macrophages are one of the immune cell types frequently found in the tumor microenvironment and exist as a heterogeneous population that includes both M1 and M2 macrophages. While the spectrum of macrophage subpopulations are likely quite diverse, traditionally, it is thought that M1 macrophages are pro-inflammatory, enhancing immune responses against tumor cells, while M2 macrophages are pro-tumor, since they express a wide array of anti-inflammatory molecules, cytokines and growth factors that promote tumor growth, angiogenesis and an immunosuppressive microenvironment. We evaluated CC-90002 efficacy in the RPMI-8226 multiple myeloma and MDA-MB-231 breast cancer xenograft models and enumerated mouse M1/M2-like macrophage populations within in the tumor before and after C-90002 treatment. In both RPMI-8226 and MDA-MB-231 models, M2 macrophages were the primary resident macrophage. Our studies show that when mice bearing RPMI-8226 multiple myeloma xenografts were treated with CC-90002 (a humanized anti-CD47 antibody), tumor regression was preceded by infiltration of macrophages into the xenograft. In the MDA-MB-231 breast cancer model, resident macrophages appeared to mediate the CC-90002 anti-tumor efficacy in vivo without additional macrophage trafficking. Interestingly, in both models, M1 macrophages appear to mediate CC-90002 efficacy regardless of whether macrophages infiltrate the tumor or are tumor-resident. In the MDA-MB-231 breast cancer model where CC-90002 did not induce infiltration, it is possible that resident tumor macrophages were re-educated to an M1 phenotype. In in vitro experiments using human monocyte-derived macrophages, both M1 and M2 macrophages are able to promote phagocytosis and additionally, we observed that CC-90002 selectively inhibited migration of M2 macrophages toward tumor cell conditioned media. This would presumably shift the overall balance of tumor-associated macrophages toward the M1 phenotype and suggests that inhibiting CD47 can both promote tumor phagocytosis and skew tumor macrophage subpopulations toward an anti-tumor phenotype. CC-90002 is currently being tested in two ongoing Phase I clinical studies in subjects with advanced solid and hematologic cancers (NCT02367196, NCT02641002). Citation Format: Bing Zheng, Piu Wong, WenQing Yang, Rama Narla, Michael Burgess, Laure Escoubet, Heather Raymon, Kandasamy Hariharan, John Boylan, Kristen Hege, Victoria Sung. CC-90002 (anti-CD47 antibody) in vivo anti-tumor activity is associated with an increase in M1-polarized macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2009. doi:10.1158/1538-7445.AM2017-2009