title: Anti-NeuGcGM3 antibodies, actively elicited by idiotypic vaccination in nonsmall cell lung cancer patients, induce tumor cell death by an oncosis-like mechanism.
abstract: 1E10 is a murine anti-idiotypic mAb specific for an idiotypic mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In melanoma, breast, and lung cancer patients, this anti-idiotypic Ab was able to induce a specific Ab response against N-glycosylated gangliosides, attractive targets for cancer immunotherapy as these glycolipids are not naturally expressed in humans. A clinical study with nonsmall cell lung cancer patients showed encouraging clinical benefits. Immunological studies performed in 20 of these patients suggested a correlation between the induction of Abs against NeuGcGM3 and longer survival times. The induced anti-NeuGcGM3 Abs recognized and directly killed tumor cells expressing the Ag, by a mechanism independent of complement activation. In the present work, we show that this cytotoxicity differs from apoptosis because it is temperature independent, no chromatin condensation or caspase 3 induction are detected, and the DNA fragmentation induced has a different pattern than the one characteristic for apoptosis. It is a very quick process and involves cytosqeleton reorganization. The Abs induce cellular swelling and the formation of big membrane lesions that allow the leakage of cytoplasm and the loss of the cell membrane integrity. All of these characteristics resemble a process of oncotic necrosis. To our knowledge, this is the first report of the active induction in cancer patients of NeuGcGM3-specific Abs able to induce complement independent oncotic necrosis to tumor cells. These results contribute to reinforcing the therapeutic potential of anti-idiotypic vaccines and the importance of NeuGcGM3 ganglioside as antitumor target.
authors.affiliation: Department of Antibody Engineering, Center of Molecular Immunology, Havana 11600, Cuba. anita@cim.sld.cu
authors.forename: Ana María
authors.initials: AM
authors.lastname: Hernández
authors.forename: Nely
authors.initials: N
authors.lastname: Rodríguez
authors.forename: Jorge E
authors.initials: JE
authors.lastname: González
authors.forename: Emma
authors.initials: E
authors.lastname: Reyes
authors.forename: Teresa
authors.initials: T
authors.lastname: Rondón
authors.forename: Tania
authors.initials: T
authors.lastname: Griñán
authors.forename: Amparo
authors.initials: A
authors.lastname: Macías
authors.forename: Sailyn
authors.initials: S
authors.lastname: Alfonso
authors.forename: Ana María
authors.initials: AM
authors.lastname: Vázquez
authors.forename: Rolando
authors.initials: R
authors.lastname: Pérez
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy / Q000648:ultrastructure; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy* / Q000648:ultrastructure; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D004285:Dogs; D005679:G(M3) Ganglioside / Q000031:analogs & derivatives* / Q000276:immunology*; D006736:Horses; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007130:Immunoglobulin Idiotypes / Q000008:administration & dosage / Q000502:physiology*; D007075:Immunoglobulin M / Q000096:biosynthesis; D007939:Leukemia L1210 / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D010954:Plasmacytoma / Q000276:immunology / Q000473:pathology / Q000628:therapy
chemical_list: D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D005679:G(M3) Ganglioside; D007074:Immunoglobulin G; D007130:Immunoglobulin Idiotypes; D007075:Immunoglobulin M; C044298:N-glycolylneuraminyllactosylceramide