Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

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Publication Year:
2022
Authors:
Johanna Theruvath, Marie Menard, Benjamin A H Smith, Miles H Linde, Garry L Coles, Guillermo Nicolas Dalton, Wei Wu, Louise Kiru, Alberto Delaidelli, Elena Sotillo, John L Silberstein, Anna C Geraghty, Allison Banuelos, Molly Thomas Radosevich, Shaurya Dhingra, Sabine Heitzeneder, Aidan Tousley, John Lattin, Peng Xu, Jing Huang, Nicole Nasholm, Andy He, Tracy C Kuo, Emma R B Sangalang, Jaume Pons, Amira Barkal, Rachel E Brewer, Kristopher D Marjon, Jose G Vilches-Moure, Payton L Marshall, Ricardo Fernandes, Michelle Monje, Jennifer R Cochran, Poul H Sorensen, Heike E Daldrup-Link, Irving L Weissman, Julien Sage, Ravindra Majeti, Carolyn R Bertozzi, William A Weiss, Crystal L Mackall, Robbie G Majzner
PubMed ID:
35027753
Funding Grants:
Public Summary:
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.
Scientific 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.