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Updated: Dec 7, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models
You Li1, Huifang Wu1, Gang Chen1
1MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Abstract:
Glioblastoma (GBM) is an aggressive malignancy with poor prognosis. New therapeutic strategies for GBM are urgently needed. Although clinical studies have demonstrated the feasibility and safety of chimeric antigen receptor (CAR) T cell therapy for GBM, its efficacy has not been that impressive. The major limitation for anti-tumor efficacy of CAR-Ts is the immunosuppressive milieu of the GBM tumor microenvironment (TME). TGFβ, a substantial component in GBM, compromises the immune response and contributes to immune evasion and tumor progression. To overcome this limitation and improve the efficacy of CAR-T cells for GBM, we optimized an EGFRvIII-specific CAR construct with TGFRII ectodomain as a TGFβ-trap and generated TGFβ-resistant CAR-Ts for GBM therapy. We demonstrated that this TGFβ-trapped architecture enhanced anti-tumor efficacy of EGFRvIII-specific CAR-T and prolonged the survival of mice bearing GBM. In addition, the GBM-infiltrated microglia, typically considered tumorigenic, showed increased expression of M1 polarization markers after treatment with the TGFβ-trap CAR-Ts group, indicating that these microglia were polarized toward a pro-inflammatory and anti-tumorigenic phenotype. Overall, these results indicated that arming CAR-T cells with a TGFβ-trap diminishes the immunosuppressive effect and is a potential strategy to improve CAR-T efficacy for GBM therapy.
Insights
Chimeric antigen receptor (CAR) T cell therapy for glioblastoma (GBM) shows promise. Engineering CAR-T cells to trap immunosuppressive TGFβ enhances their anti-tumor activity and improves survival in GBM mouse models.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, necessitating novel therapeutic approaches.
- Current chimeric antigen receptor (CAR) T cell therapy for GBM faces limitations due to the immunosuppressive tumor microenvironment (TME).
- Transforming growth factor beta (TGFβ) within the GBM TME suppresses immune responses, promoting immune evasion and tumor progression.
Purpose of the Study:
- To enhance the efficacy of CAR T cell therapy for glioblastoma.
- To overcome the immunosuppressive effects of TGFβ in the GBM TME.
- To develop TGFβ-resistant CAR T cells with improved anti-tumor activity.
Main Methods:
- Optimized an EGFRvIII-specific CAR construct by incorporating a TGFβ receptor II (TGFRII) ectodomain to act as a TGFβ-trap.
- Generated TGFβ-resistant CAR T cells for GBM therapy.
- Evaluated the anti-tumor efficacy and survival impact in mice bearing GBM xenografts.
Main Results:
- The TGFβ-trapped CAR T cell architecture significantly enhanced anti-tumor efficacy against EGFRvIII-positive GBM.
- Treatment with TGFβ-trap CAR T cells led to prolonged survival in mice with GBM.
- GBM-infiltrated microglia exhibited a shift towards a pro-inflammatory, anti-tumorigenic M1 phenotype post-treatment.
Conclusions:
- Arming CAR T cells with a TGFβ-trap effectively neutralizes the immunosuppressive TME.
- This strategy represents a promising approach to improve the therapeutic efficacy of CAR T cells for glioblastoma treatment.
- Modulating microglia polarization is a potential mechanism by which TGFβ-trap CAR T cells exert their anti-tumor effects.
