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Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Combinatorial therapy with resveratrol sensitizes glioblastoma to NKG2D CAR-T cells
Wei Liang1,2, Yexiao Tang3, Muhammad Auwal Saliu1,2
1Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Abstract:
Chimeric antigen receptor T-cell (CAR-T) therapies have shown potential in clinical trials for glioblastoma, yet treatment responses vary due to heterogeneous antigen expression and post-treatment immune escape. NKG2D-based CAR-T cells have exhibited a favorable safety profile in patients with hematologic malignancies and demonstrated potent antitumor activity in xenograft models, including those of glioblastoma. Nevertheless, glioma cells could evade immune recognition by downregulating or proteolytically shedding NKG2D ligands. To enhance the efficacy of NKG2D CAR-T therapy, we investigated its combination with preclinical agents capable of penetrating the blood-brain barrier that could upregulate NKG2D ligands on glioma cells. Our study revealed that resveratrol (RSV), a bioactive polyphenol, significantly increased the surface expression of NKG2D ligands on glioblastoma cells. RSV pretreatment sensitized these cells to NKG2D CAR-T-mediated killing in vitro. Additionally, the combination of RSV with NKG2D CAR-T cells demonstrated potent antitumor activity in vivo. Mechanistically, RSV potentially induced NKG2D ligand expression via activation of the p53 signaling pathway. These preclinical findings identify RSV as a promising pharmacological adjuvant that enhances NKG2D CAR-T efficacy in glioblastoma, supporting further translational and clinical evaluation of this combinatory approach.
Insights
Resveratrol (RSV) enhances chimeric antigen receptor T-cell (CAR-T) therapy for glioblastoma by increasing NKG2D ligand expression on cancer cells. This combination therapy shows potent antitumor effects, suggesting RSV as a promising adjuvant for glioblastoma treatment.
Area of Science:
- Immunotherapy
- Oncology
- Neuro-oncology
Background:
- Chimeric antigen receptor T-cell (CAR-T) therapy shows promise for glioblastoma but faces challenges from tumor heterogeneity and immune escape.
- NKG2D-based CAR-T cells have a good safety profile and antitumor activity, but glioma cells can evade them by downregulating NKG2D ligands.
Purpose of the Study:
- To investigate the combination of NKG2D CAR-T therapy with blood-brain barrier-penetrating agents to enhance glioblastoma treatment.
- To evaluate the potential of resveratrol (RSV) as an adjuvant to upregulate NKG2D ligands on glioblastoma cells.
Main Methods:
- Assessed the effect of resveratrol (RSV) on NKG2D ligand expression in glioblastoma cells.
- Evaluated the efficacy of RSV-pretreated glioblastoma cells against NKG2D CAR-T cells in vitro.
- Tested the in vivo antitumor activity of the combination therapy in glioblastoma models.
Main Results:
- Resveratrol (RSV) significantly increased surface expression of NKG2D ligands on glioblastoma cells.
- RSV pretreatment sensitized glioblastoma cells to NKG2D CAR-T-mediated killing in vitro.
- The combination of RSV and NKG2D CAR-T cells demonstrated potent antitumor activity in vivo.
Conclusions:
- Resveratrol (RSV) acts as a promising pharmacological adjuvant to enhance NKG2D CAR-T efficacy in glioblastoma.
- The combination therapy warrants further translational and clinical evaluation for glioblastoma treatment.
- RSV may induce NKG2D ligand expression via p53 signaling pathway activation.
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