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Updated: Nov 25, 2025
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Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography
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GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma - assessing tumor and T cell
Jatuporn Sujjitjoon1, Elias Sayour2, Shih-Ting Tsao3
1Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok 10700, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract:
A novel disialoganglioside 2 (GD2)-specific chimeric antigen receptor (CAR)-modified T cell therapy against retinoblastoma (RB) were generated. GD2-CAR consists of a single-chain variable fragment (scFv) derived from a monoclonal antibody, hu3F8, that is linked with the cytoplasmic signaling domains of CD28, 41BB, a CD3ζ, and an inducible caspase 9 death fusion partner. GD2 antigen is highly expressed in Y79RB cell line and in several surgical RB tumor specimens. In vitro co-culture experiments revealed the effective killing of Y79RB cells by GD2-CAR T cells, but not by control CD19-CAR T cells. The killing activities of GD2-CAR T cells were diminished when repeatedly exposed to the tumor, due to an attenuated expression of GD2 antigen on tumor cells and upregulation of inhibitory molecules of the PD1 and PD-L1 axis in the CAR T cells and RB tumor cells respectively. This is the first report to describe the potential of GD2-CAR T cells as a promising therapeutic strategy for RB with the indication of potential benefit of combination therapy with immune checkpoint inhibitors.
Insights
This study introduces a novel chimeric antigen receptor (CAR) T cell therapy targeting disialoganglioside 2 (GD2) for retinoblastoma (RB). GD2-CAR T cells effectively killed RB cells, suggesting a promising new treatment strategy.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Retinoblastoma (RB) is a pediatric eye cancer.
- Current treatments for RB have limitations.
- Disialoganglioside 2 (GD2) is a tumor-associated antigen highly expressed in RB.
Purpose of the Study:
- To develop and evaluate a novel chimeric antigen receptor (CAR) T cell therapy targeting GD2 for retinoblastoma.
- To assess the efficacy of GD2-CAR T cells against RB cells in vitro.
- To investigate potential mechanisms of resistance to GD2-CAR T cell therapy.
Main Methods:
- Generation of GD2-specific CAR T cells using a single-chain variable fragment (scFv) derived from the hu3F8 antibody.
- Construction of GD2-CAR incorporating CD28, 41BB, CD3ζ signaling domains, and an inducible caspase 9 suicide gene.
- In vitro co-culture experiments with Y79RB cell line and primary RB tumor specimens.
- Analysis of GD2 antigen expression and immune checkpoint molecule (PD1/PD-L1) axis in response to therapy.
Main Results:
- GD2-CAR T cells demonstrated effective killing of GD2-expressing Y79RB cells and primary RB tumor cells.
- Control CD19-CAR T cells did not exhibit significant killing activity.
- Therapeutic efficacy was diminished upon repeated tumor exposure due to reduced GD2 expression and increased PD1/PD-L1 axis activity.
- GD2 antigen expression was attenuated on tumor cells, and PD1/PD-L1 axis was upregulated.
Conclusions:
- GD2-CAR T cell therapy represents a promising novel therapeutic strategy for retinoblastoma.
- Combination therapy with immune checkpoint inhibitors may overcome resistance mechanisms.
- This approach offers a potential new avenue for treating aggressive retinoblastoma.
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