Targeting the CD47/SIRPα interaction in cancer: opportunities in non-Hodgkin lymphoma

Macrophages are attractive targets for novel cancer immunotherapy approaches since they can infiltrate into the tumor microenvironment and have the capacity to engulf and destroy cancer cells by phagocytosis. The CD47/SIRPα axis is a key immune checkpoint that regulates macrophages' ability to attack cancer cells and has been the subject of intense preclinical and clinical investigation.

We review the scientific rationale for developing CD47/SIRPα-targeting therapies, and we summarize results of recent clinical trials that tested anti-CD47 antibodies, SIRPα-Fc fusion proteins, or anti-SIRPα antibodies in patients with lymphoma. We review signs of efficacy, opportunities for combination strategies, and challenges such as on-target hematologic toxicity and an 'antigen sink' that exists due to CD47 expression on blood cells.

Multiple CD47/SIRPα-targeting therapeutics and multiple clinical trials have demonstrated encouraging results in patients with non-Hodgkin lymphoma, where objective responses have been observed in combination with rituximab and other anti-cancer agents. Next-generation approaches, such as bispecific antibodies and engineering efforts to reduce blood cell binding, are now under clinical development and may be successful strategies to unlock the extraordinary potential of the CD47/SIRPα immune checkpoint.