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https://doi.org/10.18632/oncotarget.4670
Title: | A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing | Authors: | Prapa, M Caldrer, S Spano, C Bestagno, M Golinelli, G Grisendi, G Petrachi, T Conte, P Horwitz, E.M Campana, D Paolucci, P Dominici, M |
Keywords: | aldesleukin CD137 antigen CD3 zeta antigen gamma interferon ganglioside GD2 ganglioside GD2 4 1BB chimeric antigen receptor monoclonal antibody lymphocyte antigen monoclonal antibody retrovirus vector single chain fragment variable antibody tumor necrosis factor related apoptosis inducing ligand unclassified drug CD137 antigen gamma interferon ganglioside ganglioside, GD2 green fluorescent protein lymphocyte antigen receptor single chain fragment variable antibody TNFSF10 protein, human tumor necrosis factor related apoptosis inducing ligand animal experiment animal model animal tissue antineoplastic activity apoptosis Article cancer inhibition cell based gene therapy controlled study drug cytotoxicity drug targeting genetic transduction human human cell in vitro study in vivo study lymphocytic infiltration lymphocytotoxicity mouse neuroblastoma neuroectoderm tumor nonhuman protein analysis protein expression protein secretion reverse transcription polymerase chain reaction SH SY5Y cell line SKnBE cell line T lymphocyte tumor xenograft adoptive immunotherapy animal cytotoxicity drug screening flow cytometry fluorescence microscopy genetics HEK293 cell line immunology metabolism neuroblastoma nonobese diabetic mouse pathology procedures SCID mouse transplantation tumor cell line Animals Antigens, CD137 Apoptosis Cell Line, Tumor Cytotoxicity, Immunologic Flow Cytometry Gangliosides Green Fluorescent Proteins HEK293 Cells Humans Immunotherapy, Adoptive Interferon-gamma Mice, Inbred NOD Mice, SCID Microscopy, Fluorescence Neuroblastoma Receptors, Antigen, T-Cell Single-Chain Antibodies T-Lymphocytes TNF-Related Apoptosis-Inducing Ligand Xenograft Model Antitumor Assays |
Issue Date: | 2015 | Citation: | Prapa, M, Caldrer, S, Spano, C, Bestagno, M, Golinelli, G, Grisendi, G, Petrachi, T, Conte, P, Horwitz, E.M, Campana, D, Paolucci, P, Dominici, M (2015). A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. Oncotarget 6 (28) : 24884-24894. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.4670 | Rights: | Attribution 4.0 International | Abstract: | Chimeric antigen receptor (CAR)-expressing T cells are a promising therapeutic option for patients with cancer. We developed a new CAR directed against the disialoganglioside GD2, a surface molecule expressed in neuroblastoma and in other neuroectoderm-derived neoplasms. The anti-GD2 single-chain variable fragment (scFv) derived from a murine antibody of IgM class was linked, via a human CD8a hinge-transmembrane domain, to the signaling domains of the costimulatory molecules 4-1BB (CD137) and CD3-ζ. The receptor was expressed in T lymphocytes by retroviral transduction and anti-tumor activities were assessed by targeting GD2-positive neuroblastoma cells using in vitro cytotoxicity assays and a xenograft model. Transduced T cells expressed high levels of anti-GD2 CAR and exerted a robust and specific anti-tumor activity in 4- and 48-hour cultures with neuroblastoma cells. Cytotoxicity was associated with the release of pro-apoptotic molecules such as TRAIL and IFN-γ. These results were confirmed in a xenograft model, where anti-GD2 CAR T cells infiltrating tumors and persisting into blood circulation induced massive apoptosis of neuroblastoma cells and completely abrogated tumor growth. This anti-GD2 CAR represents a powerful new tool to redirect T cells against GD2. The preclinical results of this study warrant clinical testing of this approach in neuroblastoma and other GD2-positive malignancies. | Source Title: | Oncotarget | URI: | https://scholarbank.nus.edu.sg/handle/10635/180938 | ISSN: | 19492553 | DOI: | 10.18632/oncotarget.4670 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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