Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication
Johanna Theruvath1, Marie Menard2, Benjamin A H Smith3,4
1Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.
Insights
Combining anti-disialoganglioside GD2 (GD2) antibodies with anti-CD47 immunotherapy shows potent synergy, eradicating neuroblastoma and reducing tumors in other cancers. This approach reorients macrophage activity for enhanced anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Disialoganglioside GD2 is overexpressed on neuroblastoma and other solid tumors.
- Anti-GD2 monoclonal antibodies improve outcomes in high-risk neuroblastoma but have limited efficacy in other GD2+ malignancies.
- Tumors evade immune detection by expressing CD47, a 'Don't eat me' signal that inhibits macrophage phagocytosis.
Purpose of the Study:
- To investigate the synergistic potential of combining anti-GD2 and anti-CD47 therapies.
- To elucidate the mechanisms driving the synergy between anti-GD2 and anti-CD47 in various cancer models.
Main Methods:
- Utilized syngeneic and xenograft mouse models of neuroblastoma, osteosarcoma, and small-cell lung cancer.
- Administered combination therapy of anti-GD2 and anti-CD47 antibodies.
- Analyzed macrophage activity and immune signaling pathways.
Main Results:
- The combination of anti-GD2 and anti-CD47 eradicated tumors in neuroblastoma models.
- Significant tumor burden reduction and extended survival were observed in osteosarcoma and small-cell lung cancer models.
- Synergy was attributed to GD2 ligation upregulating calreticulin ('Eat me' signal) and disrupting the GD2-Siglec-7 interaction.
Conclusions:
- The combination of anti-GD2 and anti-CD47 demonstrates potent anti-tumor activity across multiple cancer types.
- This combination strategy warrants clinical translation for treating GD2-expressing malignancies.
- CD47 blockade is most effective when combined with antibodies that modulate additional phagocytic signals.
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