First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Targeting of small-cell lung cancer using the anti-GD2 ganglioside monoclonal antibody 3F8: a pilot trial. The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): results from part II of the open-label, randomized, phase II/III distinct study. Phase II study of antidisialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma (AOST1421): a report from the Children’s Oncology Group. Outcome of children with relapsed or refractory neuroblastoma: a meta-analysis of ITCC/SIOPEN European phase II clinical trials. Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13- cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis. Biosynthesis and expression of the disialoganglioside GD2, a relevant target antigen on small cell lung carcinoma for monoclonal antibody-mediated cytolysis. A., Rosenberg, J., Mujoo, K., Hirschowitz, L. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M + diffuse midline gliomas. Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults.
Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. 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. 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 synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. 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. 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. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2 + malignancy. The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. Nature Medicine volume 28, pages 333–344 ( 2022) Cite this article
Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication
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