The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting

• Published in: British journal of cancer 2012-03, Vol.106 (6), p.1123
• Main Authors: Kailayangiri, S, Altvater, B, Meltzer, J, Pscherer, S, Luecke, A, Dierkes, C, Titze, U, Leuchte, K, Landmeier, S, Hotfilder, M, Dirksen, U, Hardes, J, Gosheger, G, Juergens, H, Rossig, C
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Antigens, Surface - immunology; Antigens, Surface - metabolism; Bone Neoplasms - immunology; Bone Neoplasms - metabolism; Bone Neoplasms - therapy; Cell Line, Tumor; Cell Proliferation; Child; Coculture Techniques; Cytotoxicity, Immunologic; Female; Gangliosides - immunology; Gangliosides - metabolism; Granzymes - secretion; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - metabolism; Sarcoma, Ewing - immunology; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - therapy; Single-Chain Antibodies - biosynthesis; Single-Chain Antibodies - metabolism; Spheroids, Cellular - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Young Adult
• ISSN: 1532-1827
• DOI: 10.1038/bjc.2012.57

Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer. We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo. Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts. G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.