A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing

Malvina Prapa, Sara Caldrer, Carlotta Spano, Marco Bestagno, Giulia Golinelli, Giulia Grisendi, Tiziana Petrachi, Pierfranco Conte, Edwin M. Horwitz, Dario Campana, Paolo Paolucci, Massimo Dominici

Research output: Contribution to journalArticlepeer-review

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-?. 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-?. 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.

Original languageEnglish
Pages (from-to)24884-24894
Number of pages11
JournalOncotarget
Volume6
Issue number28
DOIs
Publication statusPublished - 2015

Keywords

  • Anti-GD2 IgM-derived
  • Chimeric antigen receptor
  • GD2
  • Neuroblastoma
  • T lymphocytes

ASJC Scopus subject areas

  • Oncology

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