Anti-GD2 and anti-CD47 antibodies show synergy in models of neuroblastoma and osteosarcoma.

  • Major Finding: Anti-GD2 and anti-CD47 antibodies show synergy in models of neuroblastoma and osteosarcoma.

  • Concept: Treatment increases macrophage phagocytosis of tumors by reducing GD2–Siglec-7 binding and increasing surface calreticulin.

  • Impact: This combination could substantially improve survival in patients with neuroblastoma or osteosarcoma.

Antibodies targeting the disialoganglioside GD2 have been utilized in GD2-overexpressing neuroblastoma, but many patients relapse on these therapies. Furthermore, GD2-targeting antibodies have not demonstrated clinical activity in other tumor types that overexpress GD2, such as osteosarcoma. Immune evasion mechanisms that drive the poor responses to anti-GD2 antibodies have not been fully defined; therefore, Theruvath and colleagues investigated if targeting CD47, a checkpoint molecule for macrophage activity overexpressed on tumor cells, increases anti-GD2 efficacy in neuroblastoma and other GD2-overexpressing malignancies. Dual treatment with anti-GD2 and anti-CD47 showed increased macrophage phagocytosis of neuroblastoma cells with complete tumor eradication and long-term survival in aggressive in vivo neuroblastoma models as compared to single agents alone, with depletion of myeloid cells abrogating this antitumor effect. Mechanistically, GD2-specific factors were behind the enhanced antitumor activity, with GD2 ligation inhibiting GD2 binding to the inhibitory immune receptor Siglec-7 as well as upregulating the surface molecule calreticulin, a prophagocytic marker. In other GD2+ cancers, such as osteosarcoma and small cell lung cancer, anti-GD2 and anti-CD47 again showed synergy both in vitro and in vivo, demonstrating increased phagocytosis, delayed tumor growth, and prolonged survival in these models. Moreover, combination treatment also led to the eradication of nearly all metastases in a model of pulmonary metastatic osteosarcoma. Furthermore, mice implanted with orthotopic osteosarcomas treated with single agent or combination of anti-GD2 and anti-CD47 showed induction of macrophage infiltration in the combination-treated cohort as well as increased expression of inducible nitric oxide synthase, suggesting the recruitment of antitumor macrophages. A similar phenotype was observed in a model of neuroblastoma. Thus, this study provides evidence of synergy between these two antibodies, with this work leading to a first-in-human/first-in-child clinical trial (NCT04751383).

Theruvath J, Menard M, Smith BAH, Linde MH, Coles GL, Dalton GN, et al. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nat Med 2022 Jan 13 [Epub ahead of print].

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