Immune Cell Longevity via AMPK Metabolic Reprogramming
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Solution Overview
Problem
Current methods for improving the longevity of immune cells in vivo to fight diseases are inadequate, particularly in the context of cancer immunotherapy, where the persistence of modified T-cells post-transfusion is crucial but challenging to achieve.
Innovation Solution
Increasing the AMP-activated protein kinase (AMPK) activity of immune cells through genetic modification or exposure to activators, which enhances their longevity by promoting factors such as motility, mitochondrial mass, and oxidative metabolism, thereby extending their functional lifespan in vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cells are modified to enhance their anti-tumor activity, then their effectiveness in fighting cancer is improved, but their longevity and persistence in vivo deteriorates
Solution Approach 1:
The patent changes the metabolic parameters of immune cells by activating AMPK through genetic modification (overexpressing AMPKα1 or AMPKα2 subunits) or pharmacological activation (metformin treatment). This parameter change shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby extending cell longevity while preserving anti-tumor function.
Solution Approach 2:
The patent applies preliminary action by pre-modifying immune cells ex vivo to enhance their metabolic capacity and longevity before in vivo administration. The cells are genetically engineered to overexpress AMPK subunits or treated with metformin prior to infusion, so they are pre-prepared for extended persistence and sustained anti-tumor activity in the patient.
2Quantity of substance
If immune cells are expanded ex vivo to increase their numbers, then their immediate therapeutic impact is improved, but their functional lifespan and persistence in vivo deteriorates
Solution Approach 1:
The patent changes the metabolic state of expanded immune cell populations by activating AMPK during or after expansion. This metabolic reprogramming transforms the fate of expanded cells from exhaustion and senescence to sustained functionality, allowing large numbers of cells to persist long-term in vivo.
Solution Approach 2:
The patent enables continuous useful action by ensuring that expanded immune cells maintain their anti-tumor functionality over extended periods. Through AMPK activation, the cells avoid metabolic exhaustion and continue to perform anti-tumor functions continuously rather than declining after initial expansion.
Data Source
AI summary
Embodiments of the present disclosure pertain to methods of modifying immune cells by increasing the AMP-activated protein kinase (AMPK) activity of the immune cells in order to produce modified immune cells with enhanced longevity. In some embodiments, the methods of the present disclosure include one or more of the following steps: (1) obtaining immune cells from a subject; (2) increasing the AMPK activity of the immune cells; (3) expanding the modified immune cells; (4) introducing the modified immune cells to a subject; and (5) treating a disease in the subject. In further embodiments, the methods of the present disclosure include an in vivo method of increasing the AMPK activity of immune cells in a subject in order to treat a disease in the subject. Additional embodiments of the present disclosure pertain to the modified immune cells.