T Cell Selection via Low GLUT1 Expression for Anti-Cancer Activity
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Solution Overview
Problem
Current T cell therapies for cancer face challenges in optimizing the persistence and function of adoptively transferred T cells due to the hostile tumor environment, which affects their metabolic profiles and anti-tumor efficacy.
Innovation Solution
Selecting T cells with low glucose transporter 1 (GLUT1) expression levels using a GLUT1 ligand for improved anti-cancer activity, as these cells exhibit enhanced anti-tumor efficacy when transferred to tumor-bearing mice.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are adoptively transferred to treat cancer, then anti-tumor immunity is enhanced, but the hostile tumor metabolic environment reduces T cell persistence and function
Solution Approach 1:
The invention changes the metabolic parameter of T cells by selecting for low GLUT1 expression levels. This parameter change enables T cells to survive and function better in the hostile tumor environment by reducing their dependence on glucose, thereby improving both anti-tumor efficacy and persistence
Solution Approach 2:
The invention converts the harmful effect of the tumor's glucose-deprived environment into a beneficial selection criterion. By identifying and selecting T cells with low GLUT1 expression, the method exploits the metabolic constraints of the tumor environment to enrich for T cells that are naturally better adapted to survive and function within it
2Productivity
If T cells with high GLUT1 expression are used, then glucose uptake and proliferation are enhanced, but anti-cancer activity is reduced
Solution Approach 1:
Instead of selecting for high glucose transporter expression to maximize proliferation, the invention inverts the selection criterion by choosing T cells with low GLUT1 expression. This inverted approach reveals that reduced glucose dependence correlates with superior anti-cancer activity, challenging the conventional assumption that higher metabolic activity always translates to better therapeutic outcomes
3Adaptability or versatility
If the tumor metabolic environment is considered hostile, then T cell function is suppressed, but selecting for low GLUT1 expression overcomes this suppression
Solution Approach 1:
The invention identifies metabolic adaptation as a key parameter for T cell success in the tumor environment. By measuring and selecting based on GLUT1 expression levels, the method enriches for T cells that have adapted their metabolic parameters to thrive in glucose-limited conditions, thereby maintaining reliable anti-tumor function despite the hostile environment
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
T cells with low GLUT1 expression levels demonstrate improved anti-cancer activity and reduced tumor burden compared to those with high GLUT1 expression, indicating a potential biomarker for therapeutic efficacy in cancer treatment.
Implementation Method 1
contacting a population of T cells expressing GLUT1 at their cell surface, or susceptible to express GLUT1 at their cell surface, with a GLUT1 ligand
Data Source
AI summary
A method of selecting T cells with improved anti-cancer activity, the method including: a) quantifying glucose transporter 1 (GLUT1) expression level at the cell surface of a population of T cells by using a GLUT1 ligand, b) selecting T cells having a low GLUT1 expression level, wherein the T cells having a low GLUT1 expression level have improved anti-cancer activity. Also, a population of T cells with improved anti-cancer activity for use in the treatment of cancer, to the use of a GLUT1 ligand for selecting T cells with improved anti-cancer activity, and to the use of GLUT1 as a biomarker of the anti-cancer therapeutic efficacy of T cells.