Engineered Immune Cell Metabolic Flexibility
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Solution Overview
Problem
The efficacy of CAR-engineered T-cells in treating solid tumors is sub-optimal due to immunosuppressive mechanisms in the tumor microenvironment, particularly metabolic competition for glucose between tumor cells and therapeutic T-cells.
Innovation Solution
Genetically engineering immune cells to express an exogenous alternative carbon source (ACS) metabolism gene, allowing them to metabolize alternative carbon sources beyond glucose, thereby enhancing their metabolic competitiveness in tumor environments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Use of energy by moving object
If CAR-engineered T-cells rely on glucose metabolism for effector function, then they can maintain high energy production through anaerobic glycolysis, but they are outcompeted by tumor cells for glucose in the tumor microenvironment
Solution Approach 1:
The patent changes the metabolic parameter of T-cells by introducing exogenous genes that enable alternative carbon source metabolism. Specifically, T-cells are engineered to express enzymes such as pyruvate kinase M2 (PKM2) and transporters that allow utilization of non-glucose carbon sources like lactate, pyruvate, and acetate, thereby diversifying their metabolic pathways and reducing dependence on glucose
Solution Approach 2:
The patent segments the metabolic pathway by introducing separate, independent metabolic routes. Instead of relying solely on the traditional glucose-glycolysis pathway, the engineered T-cells possess distinct alternative pathways that can process different carbon sources, allowing them to switch between metabolic modes depending on environmental availability
2Reliability
If T-cells are highly reliant on glucose as a carbon source, then they can sustain anti-tumour effector function through anaerobic glycolysis, but tumor cells outcompete them for glucose in established solid tumors
Solution Approach 1:
The patent changes the metabolic parameter of T-cells by introducing exogenous genes that enable alternative carbon source metabolism. Specifically, T-cells are engineered to express enzymes such as pyruvate kinase M2 (PKM2) and transporters that allow utilization of non-glucose carbon sources like lactate, pyruvate, and acetate, thereby diversifying their metabolic pathways and reducing dependence on glucose
Solution Approach 2:
The patent segments the metabolic pathway by introducing separate, independent metabolic routes. Instead of relying solely on the traditional glucose-glycolysis pathway, the engineered T-cells possess distinct alternative pathways that can process different carbon sources, allowing them to switch between metabolic modes depending on environmental availability
3Object-generated harmful factors
If the tumor microenvironment is immunosuppressive, then the cancer can escape immune control and continue growth, but this same environment creates metabolic competition that further hinders immunotherapeutic efficacy
Solution Approach 1:
The patent converts the harmful immunosuppressive metabolic environment into a benefit by engineering T-cells to utilize the very metabolites produced by tumor cells and suppressed immune cells. Tumor cells and regulatory T-cells produce lactate, pyruvate, and other alternative carbon sources through their metabolic activity; the engineered therapeutic T-cells are equipped with enzymes and transporters to harvest these metabolites, transforming the immunosuppressive metabolic waste into fuel for anti-tumour effector function
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
The increased ability of genetically engineered immune cells to metabolize alternative carbon sources enhances their effector activity and prolongs their functional duration, potentially improving the efficacy of immunotherapy against solid tumors.
Implementation Method 1
the ability of the immune cell to metabolise the ACS is increased due to expression of the exogenous ACS metabolism gene
Data Source
AI summary
An immune cell that is genetically engineered to express an exogenous alternative carbon source (ACS) metabolism gene, in which the ACS is not glucose and wherein the ability of the immune cell to metabolise the ACS is increased due to expression of the exogenous ACS metabolism gene. Also provided are polynucleotides, vectors, pharmaceutical compositions, methods of genetically engineering the immune cell and methods of use in therapy.