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Published on: February 17, 2022
A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing
Malvina Prapa1, Sara Caldrer2, Carlotta Spano1
1Department of Medical and Surgical Sciences for Children & Adults, Division of Oncology, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
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 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.
Insights
Researchers developed a novel chimeric antigen receptor (CAR) T-cell therapy targeting disialoganglioside GD2. This therapy shows potent anti-tumor activity against neuroblastoma, warranting clinical investigation for GD2-positive cancers.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy offers a promising avenue for cancer treatment.
- Disialoganglioside GD2 is a key surface antigen expressed in neuroblastoma and other neuroectodermal tumors.
Purpose of the Study:
- To develop and evaluate a novel CAR T-cell therapy targeting the GD2 antigen for neuroblastoma treatment.
- To assess the in vitro and in vivo anti-tumor efficacy of GD2-specific CAR T cells.
Main Methods:
- Engineered T cells with a CAR targeting GD2, incorporating a single-chain variable fragment (scFv), CD8α hinge-transmembrane domain, and 4-1BB/CD3-ζ signaling domains.
- Utilized retroviral transduction for CAR expression in T lymphocytes.
- Assessed anti-tumor activity through in vitro cytotoxicity assays and a neuroblastoma xenograft mouse model.
Main Results:
- Transduced T cells expressed high levels of the anti-GD2 CAR.
- Demonstrated robust and specific in vitro anti-tumor activity against GD2-positive neuroblastoma cells, with associated TRAIL and IFN-γ release.
- In vivo studies showed CAR T cells infiltrating tumors, persisting in circulation, inducing neuroblastoma cell apoptosis, and completely inhibiting tumor growth.
Conclusions:
- The developed anti-GD2 CAR T-cell therapy is a potent tool for redirecting T cells against GD2-expressing cancers.
- Preclinical data strongly support the clinical evaluation of this CAR T-cell approach for neuroblastoma and other GD2-positive malignancies.
