The promise of macrophage directed checkpoint inhibitors in myeloid malignancies.

ABSTRACT

To date, many of the most successful checkpoint inhibitor-based therapies in cancer have targeted T-cells and adaptive immunity. However, there is an ongoing search for novel checkpoints with targeting innate immunity via activation of macrophage phagocytosis representing an exciting therapeutic strategy. CD47 is the dominant negative macrophage immune checkpoint expressed on cancer cells which acts as a "don't eat me signal", preventing phagocytosis via its interaction with SIRP-α on macrophages. CD47 has been shown to be upregulated in many cancer types including myeloid malignancies with increased expression associated with inferior OS. Magrolimab, an anti-CD47 antibody, has shown proof-of-principle of efficacy in this therapeutic class with promising early results in both higher risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML). The toxicity profile to date has been shown safe and manageable with on-target anemia related to CD47 being present on aged red blood cells and without evidence of immune related toxicities. Investigation of novel agents targeting this pathway and novel combinations are ongoing. New strategies targeting macrophage checkpoints are encouraging and likely will lead a paradigm shift in the current treatment of myeloid malignancies.