A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing
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Malvina Prapa1, Sara Caldrer2, Carlotta Spano1, Marco Bestagno3, Giulia Golinelli1, Giulia Grisendi1, Tiziana Petrachi1, Pierfranco Conte4, Edwin M. Horwitz5, Dario Campana6, Paolo Paolucci1,*, Massimo Dominici1,*
1Department of Medical and Surgical Sciences for Children & Adults, Division of Oncology, University-Hospital of Modena and Reggio Emilia, Modena, Italy
2Department of Pathology and Diagnostics, University of Verona, Verona, Italy
3International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
4Istituto Oncologico Veneto, Padova, Italy
5Departments of Pediatrics and Medicine, Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio, USA
6Department of Pediatrics, National University of Singapore, Singapore
*These authors have contributed equally to this work
Massimo Dominici, e-mail: firstname.lastname@example.org
Keywords: GD2, chimeric antigen receptor, anti-GD2 IgM-derived, neuroblastoma, T lymphocytes
Received: May 11, 2015 Accepted: July 08, 2015 Published: July 20, 2015
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 CD8α 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.
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