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Updated: Aug 1, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells
Haidy A Saleh1, Nicola Mitwasi1, Martin Ullrich1
1Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
Abstract:
Glioblastoma (GBM) is still an incurable tumor that is associated with high recurrence rate and poor survival despite the current treatment regimes. With the urgent need for novel therapeutic strategies, immunotherapies, especially chimeric antigen receptor (CAR)-expressing T cells, represent a promising approach for specific and effective targeting of GBM. However, CAR T cells can be associated with serious side effects. To overcome such limitation, we applied our switchable RevCAR system to target both the epidermal growth factor receptor (EGFR) and the disialoganglioside GD2, which are expressed in GBM. The RevCAR system is a modular platform that enables controllability, improves safety, specificity and flexibility. Briefly, it consists of RevCAR T cells having a peptide epitope as extracellular domain, and a bispecific target module (RevTM). The RevTM acts as a switch key that recognizes the RevCAR epitope and the tumor-associated antigen, and thereby activating the RevCAR T cells to kill the tumor cells. However, in the absence of the RevTM, the RevCAR T cells are switched off. In this study, we show that the novel EGFR/GD2-specific RevTMs can selectively activate RevCAR T cells to kill GBM cells. Moreover, we show that gated targeting of GBM is possible with our Dual-RevCAR T cells, which have their internal activation and co-stimulatory domains separated into two receptors. Therefore, a full activation of Dual-RevCAR T cells can only be achieved when both receptors recognize EGFR and GD2 simultaneously via RevTMs, leading to a significant killing of GBM cells both in vitro and in vivo.
Insights
A novel switchable immunotherapy system, RevCAR T cells, effectively targets glioblastoma (GBM) by dual-targeting epidermal growth factor receptor (EGFR) and GD2. This system enhances safety and specificity, showing significant GBM cell killing in vitro and in vivo.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Glioblastoma (GBM) remains an incurable brain tumor with high recurrence and poor survival rates.
- Current immunotherapies, like chimeric antigen receptor (CAR) T cells, show promise but can cause severe side effects.
- There is a critical need for safer and more specific therapeutic strategies for GBM.
Purpose of the Study:
- To develop and evaluate a novel, switchable immunotherapy system for targeting glioblastoma (GBM).
- To assess the efficacy and safety of the RevCAR system targeting both epidermal growth factor receptor (EGFR) and disialoganglioside GD2 in GBM.
- To investigate the potential of Dual-RevCAR T cells for gated targeting of GBM.
Main Methods:
- Application of a modular, switchable RevCAR system comprising RevCAR T cells and bispecific target modules (RevTMs).
- Design of novel EGFR/GD2-specific RevTMs to activate RevCAR T cells upon binding to tumor antigens.
- Utilized Dual-RevCAR T cells with separated activation and co-stimulatory domains for gated targeting.
- Evaluated GBM cell killing efficacy both in vitro and in vivo.
Main Results:
- EGFR/GD2-specific RevTMs selectively activated RevCAR T cells to kill GBM cells.
- Dual-RevCAR T cells demonstrated gated targeting, requiring simultaneous recognition of EGFR and GD2 via RevTMs for full activation.
- Significant killing of GBM cells was observed both in vitro and in vivo using the Dual-RevCAR T cell system.
Conclusions:
- The switchable RevCAR system offers a controllable, safer, and more specific approach for GBM immunotherapy.
- Dual-targeting of EGFR and GD2 with the RevCAR system shows significant potential for treating glioblastoma.
- Gated targeting with Dual-RevCAR T cells provides enhanced specificity and efficacy against GBM.
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