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Published on: December 3, 2020
Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα
AbdelAziz R Jalil1,2, Jason C Andrechak2,3, Dennis E Discher2,3
1Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
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.
Insights
The CD47-SIRPα macrophage checkpoint interaction is a cancer therapy target. Combination therapies, particularly anti-CD47 with rituximab, show promise against lymphomas.
Area of Science:
- Immunology
- Cancer Biology
- Drug Development
Background:
- The CD47-SIRPα axis is an anti-phagocytic checkpoint involving macrophages and various cell types, including cancer cells.
- Antibodies targeting CD47 or SIRPα are in development as cancer therapeutics.
Purpose of the Study:
- To review clinical trials and preclinical data on CD47 blockade in cancer therapy.
- To examine the interaction and structural features of CD47-SIRPα.
Main Methods:
- Review of preclinical and clinical trial data.
- Analysis of CD47-SIRPα interaction and structural characteristics.
Main Results:
- CD47 blockade as monotherapy shows limited efficacy in human trials, except for specific lymphomas.
- Preclinical studies in mouse models suggest efficacy, but these models may be less representative of human tumors.
- Combination therapy of anti-CD47 with rituximab demonstrates efficacy in human lymphoma trials.
Conclusions:
- The CD47-SIRPα checkpoint is a viable target, especially in combination therapies.
- Combination strategies, like anti-CD47 with rituximab, hold significant promise for treating hematological malignancies such as lymphoma.
