Cancer immunotherapy targeting the CD47/SIRPα axis

The success of cancer immunotherapy has generated tremendous interest in identifying new immunotherapeutic targets. To date, the majority of therapies have focussed on stimulating the adaptive immune system to attack cancer, including agents targeting CTLA4 and the PD-1/PD-L1 axis. However, macrophages and other myeloid immune cells offer much promise as effectors of cancer immunotherapy. The CD47/signal regulatory protein alpha (SIRP alpha) axis is a critical regulator of myeloid cell activation and serves a broader role as a myeloid-specific immune checkpoint. CD47 is highly expressed on many different types of cancer, and it transduces inhibitory signals through SIRP alpha on macrophages and other myeloid cells. In a diverse range of preclinical models, therapies that block the CD47/SIRP alpha axis stimulate phagocytosis of cancer cells in vitro and anti-tumour immune responses in vivo. A number of therapeutics that target the CD47/SIRP alpha axis are under preclinical and clinical investigation. These include anti-CD47 antibodies, engineered receptor decoys, anti-SIRP alpha antibodies and bispecific agents. These therapeutics differ in their pharmacodynamic, pharmacokinetic and toxicological properties. Clinical trials are underway for both solid and haematologic malignancies using anti-CD47 antibodies and recombinant SIRP alpha proteins. Since the CD47/SIRP alpha axis also limits the efficacy of tumour-opsonising antibodies, addi-. tional trials will examine their potential synergy with agents such as rituximab, cetuximab and trastuzumab. Phagocytosis in response to CD47/SIRP alpha-blocking agents results in antigen uptake and presentation, thereby linking the innate and adaptive immune systems. CD47/SIRP alpha blocking therapies may therefore synergise with immune checkpoint inhibitors that target the adaptive immune system. As a critical regulator of macrophage phagocytosis and activation, the potential applications of CD47/SIRP alpha blocking therapies extend beyond human cancer. They may be useful for the treatment of infectious disease, conditioning for stem cell transplant, and many other clinical indications. (C) 2017 Elsevier Ltd. All rights reserved.