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Updated: Oct 4, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to
Mahdi Abdoli Shadbad1,2,3, Nima Hemmat2, Vahid Khaze Shahgoli2,4
1Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Background:
Programmed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration of anti-PD-1 with CAR-T cells and PD-1 gene-editing of CAR-T cells have been suggested to disrupt this inhibitory axis. Herein, we aim to investigate the advantages and disadvantages of these two approaches and propose a novel strategy to ameliorate the prognosis of glioma patients.
Methods:
Scopus, Embase, and Web of Science were systematically searched to obtain relevant peer-reviewed studies published before March 7, 2021. Then, the current study was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. The random-effect model was applied to evaluate the effect size of administrated agents on the survival of animal models bearing gliomas using RevMan version 5.4. The Cochran Q test and I2 were performed to assess the possible between-study heterogeneity. Egger's and Begg and Mazumdar's tests were performed to objectively assess potential asymmetry and publication bias using CMA version 2.
Results:
Anti-PD-1 can substantially increase the survival of animal models on second-generation CAR-T cells. Also, PD-1 knockdown can remarkably prolong the survival of animal models on third-generation CAR-T cells. Regardless of the CAR-T generations, PD-1 gene-edited CAR-T cells can considerably enhance the survival of animal-bearing gliomas compared to the conventional CAR-T cells.
Conclusions:
The single-cell sequencing of tumoral cells and cells residing in the tumor microenvironment can provide valuable insights into the patient-derived neoantigens and the expression profile of inhibitory immune checkpoint molecules in tumor bulk. Thus, single-cell sequencing-guided fourth-generation CAR-T cells can cover patient-derived neoantigens expressed in various subpopulations of tumoral cells and inhibit related inhibitory immune checkpoint molecules. The proposed approach can improve anti-tumoral immune responses, decrease the risk of immune-related adverse events, reduce the risk of glioma relapse, and address the vast inter-and intra-heterogeneity of gliomas.
Insights
Programmed cell death protein 1 (PD-1) inhibits CAR-T cell anti-tumor activity. PD-1 gene-editing of CAR-T cells significantly improves survival in glioma models, offering a promising strategy for cancer therapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Programmed cell death protein 1 (PD-1) attenuates chimeric antigen receptor-T (CAR-T) cell anti-tumoral immune responses.
- Co-administration of anti-PD-1 or PD-1 gene-editing of CAR-T cells are strategies to disrupt this inhibitory axis.
- Investigating the advantages and disadvantages of these approaches aims to improve glioma patient prognosis.
Approach:
- A systematic literature search was conducted across Scopus, Embase, and Web of Science for relevant studies published before March 7, 2021.
- Meta-analysis using a random-effect model evaluated the impact of anti-PD-1 and PD-1 gene-editing on glioma-bearing animal model survival.
- Statistical methods assessed heterogeneity and publication bias.
Key Points:
- Anti-PD-1 therapy significantly increased survival in animal models receiving second-generation CAR-T cells.
- PD-1 knockdown remarkably prolonged survival in animal models treated with third-generation CAR-T cells.
- PD-1 gene-edited CAR-T cells consistently enhanced survival in glioma-bearing animals compared to conventional CAR-T cells.
Conclusions:
- Single-cell sequencing can guide the development of fourth-generation CAR-T cells targeting neoantigens and inhibitory molecules.
- This novel strategy may enhance anti-tumoral immune responses and reduce glioma relapse risk.
- The proposed approach addresses glioma heterogeneity and may decrease immune-related adverse events.
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