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The promise of macrophage directed checkpoint inhibitors in myeloid malignancies
David M Swoboda1, David A Sallman1
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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.
Insights
Targeting the CD47 "don't eat me" signal on cancer cells with magrolimab activates macrophage phagocytosis. This novel immunotherapy shows promise for myeloid malignancies like myelodysplastic syndromes and acute myeloid leukemia.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Checkpoint inhibitor therapies have primarily focused on adaptive immunity.
- Activating innate immunity, specifically macrophage phagocytosis, presents a new therapeutic avenue.
- CD47 acts as a macrophage immune checkpoint, inhibiting phagocytosis and is upregulated in various cancers.
Purpose of the Study:
- To explore the therapeutic potential of targeting the CD47 immune checkpoint.
- To evaluate the efficacy and safety of magrolimab, an anti-CD47 antibody, in myeloid malignancies.
- To investigate novel strategies for activating macrophage phagocytosis in cancer treatment.
Main Methods:
- Utilizing magrolimab, an antibody targeting the CD47 protein.
- Assessing the interaction between CD47 on cancer cells and SIRP-α on macrophages.
- Clinical evaluation of magrolimab in patients with higher-risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML).
Main Results:
- Magrolimab demonstrated proof-of-principle efficacy in early trials.
- Promising results were observed in higher-risk MDS and TP53 mutant AML.
- The treatment exhibited a safe and manageable toxicity profile, primarily on-target anemia, with no immune-related toxicities.
Conclusions:
- Targeting the CD47-SIRP-α axis is a promising strategy for activating innate immunity.
- Magrolimab offers a potential new treatment paradigm for myeloid malignancies.
- Further investigation of CD47-targeting agents and combinations is warranted.
