T Cell Metabolic Reprogramming for Persistence
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Solution Overview
Problem
Current adoptive immunotherapy strategies for treating diseases like cancer face limitations due to cumbersome T cell manufacturing processes, resulting in short-lived T cell survival and persistence, and poor expansion in vivo, making existing therapies unsuitable for widespread clinical use.
Innovation Solution
The use of metabolic enhancers such as PDHK1 inhibitors, PDP activators, and PGC1α polypeptides during the activation, transduction, and culturing of immune effector cells redirects glucose metabolism towards mitochondrial oxidation, enhancing respiratory capacity and mitochondrial mass, leading to improved T cell survival, expansion, and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional T cell activation and expansion methods are used, then therapeutic doses of T cells can be generated, but the T cells exhibit short-lived survival, lack of persistence, and poor in vivo expansion
Solution Approach 1:
The patent changes the metabolic parameters of T cells by modulating glycolysis and promoting oxidative phosphorylation. This is achieved through culturing T cells under specific conditions that favor mitochondrial metabolism, thereby altering the energy metabolism pathway from glycolytic to oxidative, which enhances T cell persistence and survival without compromising expansion capacity
Solution Approach 2:
The patent replaces the traditional mechanical/cumbersome cloning and multiple activation/expansion rounds with a metabolic modulation approach. By using metabolic enhancers and controlling culture conditions to promote oxidative metabolism, the method substitutes complex procedural steps with a biochemical parameter adjustment strategy
2Quantity of substance
If multiple rounds of activation and expansion are performed to achieve therapeutically relevant T cell numbers, then sufficient T cell dosage is obtained, but the process becomes labor intensive and expensive
Solution Approach 1:
The patent applies parameter changes by modifying the metabolic state of T cells during culture through controlled enhancement of oxidative phosphorylation. This metabolic parameter adjustment allows for more efficient expansion in fewer rounds, reducing manufacturing complexity and cost while achieving therapeutically relevant dosages
Solution Approach 2:
The patent promotes continuous oxidative metabolism throughout the T cell expansion process rather than relying on discrete activation/expansion cycles. This continuous metabolic support enables sustained T cell proliferation and survival, reducing the need for multiple intervention steps
3Quantity of substance
If T cells are activated and expanded using conventional methods, then T cell numbers increase, but the T cells undergo substantial differentiation and lose effector immune cell function
Solution Approach 1:
The patent changes the metabolic parameter profile of expanding T cells by promoting oxidative phosphorylation and modulating glycolysis. This metabolic reprogramming maintains T cells in a functional state that preserves effector capabilities while enabling expansion, preventing the functional exhaustion that occurs with conventional activation methods
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
This approach results in T cells with increased respiratory capacity and mitochondrial mass, enhancing their therapeutic efficacy in treating cancer and other diseases by improving their ability to persist and function in vivo.
Implementation Method 1
redirects glucose to the mitochondria away from fermentation into lactate (e.g., towards oxidation)
Implementation Method 2
redirects glucose to the mitochondria away from fermentation into lactate (e.g., towards oxidation)
Implementation Method 3
peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) polypeptides or variants thereof, and PGC1a agonists
Data Source
AI summary
Provided are improved methods for making immune effector cells, as well as improved immune effector cells generated using the methods. The improved T cells have improved respiratory capacity and mitochondrial mass. Adoptive T cell immunotherapies using such cells demonstrate improved survival, expansion, and persistence in vivo.