Engineered T Cells Modulating Metabolic Pathways for Persistence
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Solution Overview
Problem
Current adoptive cell therapies face challenges in improving the persistence and survival of engineered immune cells, particularly in tumor microenvironments characterized by metabolic and immunosuppressive conditions, leading to limited therapeutic efficacy.
Innovation Solution
Engineered immune cells, such as T cells, are modified to express recombinant molecules that modulate metabolic pathways, including lipid metabolism, oxidative phosphorylation, and glycolysis, to enhance their survival and persistence, while also promoting a memory-like phenotype and reducing exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If engineered immune cells are administered to treat tumors, then therapeutic efficacy is improved, but persistence and survival of the cells in the tumor microenvironment deteriorate
Solution Approach 1:
The patent modifies metabolic parameters within engineered immune cells by introducing recombinant molecules that alter metabolic pathway activity. This enables cells to adapt their metabolic state in response to tumor microenvironment conditions, thereby improving both therapeutic efficacy and persistence. The metabolic reprogramming allows cells to maintain functionality under nutrient-deprived and immunosuppressive conditions that would otherwise limit their survival duration.
2Duration of action of stationary object
If engineered immune cells are modified to enhance survival, then persistence is improved, but complexity of cellular engineering increases
Solution Approach 1:
The recombinant molecules introduced into engineered immune cells serve multiple functions simultaneously: they modulate metabolic pathways to enhance survival, maintain cellular energy homeostasis, and support persistent antigen-specific responses. This multi-functionality reduces the need for separate engineering modifications for each function, thereby limiting the increase in overall engineering complexity while achieving improved persistence.
3Reliability
If metabolic pathways are modulated to promote memory phenotype, then functional recall responses are improved, but energy resources required increase
Solution Approach 1:
The metabolic modulation system is designed to be dynamic rather than static, allowing engineered immune cells to flexibly adjust their metabolic resource allocation based on environmental cues and activation state. During rest periods, cells optimize for memory phenotype maintenance with lower energy consumption, while upon reactivation, they can rapidly upregulate metabolic pathways to support robust functional recall responses, thereby efficiently managing energy resources across different functional states.
Data Source
AI summary
Provided are cells, e.g., engineered immune cells, expressing recombinant or engineered molecules involved in metabolic pathways, such as those that promote or inhibit one or more metabolic steps, reactions, or pathways, for example, in T cells. Such molecules include those that induce or repress a particular functional outcome or metabolic event, for example, one that promotes differentiation or reprogramming into a particular phenotypic state, such as memory, long-lived, activated or activatable, non-exhausted, phenotype or stem-like phenotype. The cells generally further express an immune receptor, such as an antigen receptor, which may be an engineered receptor, such as a CAR or recombinant TCR, or may be a natural immune receptor. Also provided are cells, such as T cells, expressing such molecules and combinations thereof, compositions comprising such cells, nucleic acids such as vectors encoding the same, and methods of administration to subjects in adoptive cell therapy.