SUMMARY OF INVENTION
The tumor microenvironment (TME) is nutrient-depleted, severely limiting the effectiveness of T-cell-based immunotherapies that rely heavily on glycolysis for their anti-tumor function. MSK investigators have developed a novel metabolic engineering approach that enables immune cells to utilize fructose as an alternative fuel source through GLUT5 (glucose transporter 5) expression.
Scientists at MSK have engineered T-cells, CAR T-cells, and macrophages with GLUT5 to efficiently metabolize fructose, enabling robust anti-tumor activity even in glucose-limited conditions. GT5 (GLUT5-engineered) cells demonstrate enhanced fructolytic activity, improved cytotoxicity, and significantly improved tumor control in multiple preclinical models.
This metabolic reprogramming allows immune cells to bypass glucose scarcity in the TME and maintain high glycolytic flux through fructose utilization, leading to enhanced effector functions and improved therapeutic outcomes.
ADVANTAGES
- Overcomes nutrient limitation barrier: GT5 cells efficiently utilize fructose when glucose is scarce, maintaining robust anti-tumor activity in the nutrient-depleted TME.
- Enhanced metabolic flexibility: Engineered cells can metabolize both glucose and fructose, providing metabolic redundancy and improved persistence.
- Superior in vivo efficacy: GT5 CAR T cells demonstrate significantly improved tumor control and survival outcomes across multiple cancer models.
- Broad applicability: Platform technology applicable to multiple cell therapy modalities, including CAR T-cells, adoptive T-cell therapy, and macrophage-based therapies.
- Leverages endogenous fructose: Most patients already have adequate fructose levels from dietary sources, eliminating the need for complex supplementation protocols.
- Preserved T-cell function: Maintains key metabolic pathways (glycolysis, TCA cycle, PPP) and reduces exhaustion markers (PD-1, TIM-3).
MARKET OPPORTUNITY
Cell-based immunotherapies represent a growing market, with CAR T-cell therapy market alone valued at over $5 billion annually. However, solid tumor applications remain limited due to the hostile TME, including glucose depletion. This metabolic engineering approach addresses a fundamental barrier affecting all solid tumor immunotherapies.
PATENT INFORMATION
US National (18/708,163) and European (22890879.4) patent applications filed November 2022.
PUBLICATION
Schild et al., 2025 ” Metabolic engineering to facilitate anti-tumor immunity,” Cancer Cell.
LEAD INVESTIGATORS
- Kayvan Keshari, PhD, Fred Lebow Chair; and Director, Center for Molecular Imaging and Bioengineering, MSK
- Justin Perry, PhD, Associate Member, Immunology Program, Sloan Kettering Institute, MSK
CONTACT INFORMATION
James Delorme, PhD
Senior Licensing Manager
E-mail: delormej@mskcc.org