AP-1 Engineered T Cells for Resistance to Exhaustion
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
T cell exhaustion, characterized by marked changes in metabolic function, transcriptional programming, and loss of effector function, is a significant barrier to the efficacy of chimeric antigen receptor (CAR) T cells in treating cancer and chronic infections, limiting their effectiveness in a majority of patients.
Innovation Solution
Engineering T cells to overexpress activator protein 1 (AP-1) transcription factors, such as c-Jun, and/or reduce the expression and activity of AP-1 inhibitory complex members, enhances T cell functionality and resistance to exhaustion, thereby improving their antitumor and anti-infective capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are activated through persistent antigen exposure to enhance antitumor effects, then T cell effector function is improved, but T cell exhaustion occurs leading to loss of functionality
Solution Approach 1:
The patent modifies T cells by introducing genetic modifications that alter their transcriptional programming and metabolic parameters. Specifically, the invention changes the expression levels of key transcription factors and metabolic enzymes to prevent exhaustion while maintaining effector function during persistent antigen exposure.
Solution Approach 2:
The patent introduces intermediary molecular mechanisms that mediate between T cell activation and exhaustion prevention. This includes utilizing specific transcription factors and metabolic pathways as intermediaries to translate antigen exposure into sustained functionality without triggering exhaustion.
2Duration of action of stationary object
If CAR T cells are engineered to enhance expansion and persistence, then long-term disease control is improved, but T cell exhaustion is accelerated
Solution Approach 1:
The patent alters key parameters of CAR T cell biology including metabolic rate, transcriptional activity, and differentiation state to achieve sustained persistence without exhaustion. The invention modifies the balance between effector and memory phenotypes to maintain long-term functionality.
Solution Approach 2:
The patent creates dynamically adaptable CAR T cells that can adjust their functional state in response to persistent antigen exposure. The modified T cells exhibit enhanced plasticity in their metabolic and transcriptional programs, allowing them to maintain functionality throughout long-term persistence.
3Productivity
If T cells are exposed to high antigen density to achieve optimal CAR function, then antitumor activity is enhanced, but T cell exhaustion occurs more rapidly
Solution Approach 1:
The patent modifies T cell parameters to increase their resistance to exhaustion under high antigen density conditions. This includes altering metabolic parameters to improve energy efficiency and transcriptional parameters to maintain functionality despite continuous stimulation.
Solution Approach 2:
The patent creates T cells that can function effectively as short-lived effector cells without transitioning to the exhausted state. The modified T cells achieve high productivity during their active phase without requiring long-term persistence, effectively bypassing the exhaustion pathway.
Data Source
AI summary
The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides T cells that are modified (e.g., genetically and/or functionally) to maintain functionality under conditions in which unmodified T cells display exhaustion. Compositions and methods disclosed herein find use in preventing exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as non-engineered T cells thereby enhancing T cell function (e.g., activity against cancer or infectious disease).