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Updated: Aug 5, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
GD2 CAR-T cells in combination with Nivolumab exhibit enhanced antitumor efficacy
Guangji Zhang1, Yu Zhao1, Zhongfeng Liu1
1National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing 100069, China.
Abstract:
Glioblastoma (GBM) is a common primary brain tumor with poor clinical prognosis. Although CAR-T therapy has been trialed for treatment of GBM, the outcomes are sub-optimal possibly due to exhaustion of T cells and life-threatening neurotoxicity. To address these issues, a combined therapeutic strategy was tested in the current study using GD2 CAR-T together with Nivolumab - an anti-PD-1 monoclonal antibody. An effector-to-target co-culture system was established to evaluate the short-term and long-term cytotoxicity of CAR-T, as well as to investigate the inhibitory activity and T cell exhaustion associated with the PD-1/PD-L1 signaling pathway. Orthotopic NOD/SCID GBM animal models were generated to evaluate the safety and efficacy of the combined therapeutic strategy at various dosages of GD2 CAR-T with Nivolumab. GD2 CAR-T exhibited significant antigen-specific cytotoxicity in a dose-dependent manner in vitro. The persistence of cytotoxicity of GD2 CAR-T could be enhanced by addition of Nivolumab in the co-culture system. Animal studies suggested that GD2 CAR-T effectively infiltrated into tumor tissue and significantly hampered tumor progression. The optimal therapeutic outcome was obtained via using the medium dosage of CAR-T with Nivolumab, which displayed the highest efficacy in extending the survival up to 60 days. Further investigation of toxicity revealed that high-dosage of GD2 CAR-T could induce tumor apoptosis through p53/caspase-3/PARP signaling pathway. This study suggests that GD2 CAR-T in combination with Nivolumab may offer an improved therapeutic strategy for treatment of GBM.
Insights
Combining GD2 CAR-T therapy with Nivolumab improves glioblastoma treatment. This novel approach enhances T cell persistence and reduces tumor progression, offering a promising strategy for brain tumors.
Area of Science:
- Immunotherapy
- Oncology
- Neuro-oncology
Background:
- Glioblastoma (GBM) presents a poor prognosis, with current CAR-T therapy showing suboptimal outcomes due to T cell exhaustion and neurotoxicity.
- The PD-1/PD-L1 pathway is implicated in T cell exhaustion, a key challenge in effective CAR-T therapy for GBM.
Purpose of the Study:
- To evaluate a combined therapeutic strategy using GD2 CAR-T cells and Nivolumab (anti-PD-1 antibody) for GBM treatment.
- To assess the impact of this combination on CAR-T cell cytotoxicity, persistence, and T cell exhaustion in vitro and in vivo.
Main Methods:
- In vitro co-culture systems to evaluate GD2 CAR-T cytotoxicity and the effect of Nivolumab on T cell persistence.
- Orthotopic NOD/SCID GBM animal models were used to assess the safety and efficacy of combined therapy at various dosages.
Main Results:
- GD2 CAR-T demonstrated dose-dependent, antigen-specific cytotoxicity in vitro, with enhanced persistence when combined with Nivolumab.
- In vivo studies showed GD2 CAR-T infiltration into tumors, significantly hindering progression. Medium dosage of the combination therapy yielded optimal survival extension up to 60 days.
- High-dose GD2 CAR-T induced tumor apoptosis via the p53/caspase-3/PARP pathway, indicating a potential mechanism for tumor cell death.
Conclusions:
- The combination of GD2 CAR-T and Nivolumab offers a potentially improved therapeutic strategy for glioblastoma.
- This combined approach addresses key limitations of CAR-T therapy, including T cell exhaustion and efficacy, suggesting a path towards better clinical outcomes for GBM patients.
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