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Updated: May 21, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term
Areej Akhtar1, Md Shakir1, Mohammad Sufyan Ansari1
1Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, New Delhi, India.
Abstract:
Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
Insights
Metabolically reprogrammed CAR T-cells (MCAR) enhance anti-tumor efficacy by boosting autophagy and mitophagy. This strategy improves T-cell persistence and reduces risks associated with cytokine release syndrome.
Area of Science:
- Immunology
- Cell Biology
- Metabolic Engineering
Background:
- Chimeric antigen receptor (CAR) T-cell therapy faces challenges with tumor antigen exposure, which impairs T-cell metabolism, persistence, and efficacy.
- Enhancing T-cell metabolic fitness is crucial for overcoming these limitations and improving therapeutic outcomes.
Purpose of the Study:
- To develop metabolically reprogrammed CAR T-cells (MCAR) with enhanced autophagy and mitophagy to improve CAR T-cell function and durability.
- To identify compounds that synergistically enhance autophagy and mitophagy in CAR T-cells.
Main Methods:
- Compound screening identified a synergy between GLP-1R agonist (semaglutide) and Urolithin A to activate autophagy and mitophagy.
- MCAR T-cells (MCAR T-1) were engineered to enhance these pathways, maintaining mitochondrial metabolism.
- GLP-1-secreting MCAR T-cells (MCAR T-2) were developed for sustained memory and stemness.
Main Results:
- MCAR T-1 cells demonstrated increased CD8+ T memory cells (Tm), enhanced in vitro and in vivo anti-tumor activity, and improved persistence.
- GLP-1R knockdown confirmed the critical role of GLP-1R in autophagy/mitophagy induction.
- MCAR T-2 cells exhibited sustained memory, stemness, long-term persistence, reduced cytokine release syndrome (CRS) risks, and potent anti-tumor effects.
Conclusions:
- Metabolic reprogramming targeting autophagy and mitophagy pathways can significantly improve CAR T-cell therapy outcomes.
- MCAR T-cells offer a promising strategy for durable and effective cancer treatment by enhancing T-cell persistence and function.
