Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα structure–function

The macrophage checkpoint is an anti-phagocytic interaction between signal regulatory protein alpha (SIRPα) on a macrophage and CD47 on all types of cells – ranging from blood cells to cancer cells. This interaction has emerged over the last decade as a potential co-target in cancer when combined with other anti-cancer agents, with antibodies against CD47 and SIRPα currently in preclinical and clinical development for a variety of hematological and solid malignancies. Monotherapy with CD47 blockade is ineffective in human clinical trials against many tumor types tested to date, except for rare cutaneous and peripheral lymphomas. In contrast, pre-clinical results show efficacy in multiple syngeneic mouse models of cancer, suggesting that many of these tumor models are more immunogenic and likely artificial compared to human tumors. However, combination therapies in humans of anti-CD47 with agents such as the anti-tumor antibody rituximab do show efficacy against liquid tumors (lymphoma) and are promising. Here, we review such trials as well as key interaction and structural features of CD47-SIRPα.