Engineered T Cells With c-Jun Resist Antigen Exhaustion
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Solution Overview
Problem
Existing T cell therapies face challenges due to T cell exhaustion, characterized by metabolic changes, loss of effector functions, and increased expression of inhibitory receptors, leading to reduced persistence and efficacy in cancer treatment.
Innovation Solution
Engineered T cells with reduced Regnase-1 or PTPN2 expression and overexpressing c-Jun, combined with a recombinant antigen receptor, to enhance T cell survival and cytotoxicity, alleviating T cell exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are engineered to express antigen receptors for continuous tumor antigen exposure, then tumor-killing potency is improved, but T cell exhaustion occurs leading to reduced persistence and loss of effector functions
Solution Approach 1:
The patent changes the molecular parameters of T cells by overexpressing c-Jun (a transcription factor) and knocking down Regnase-1 or PTPN2 (negative regulators). This parameter change transforms the T cell's transcriptional program and metabolic state, enabling sustained effector function without exhaustion despite continuous antigen exposure.
Solution Approach 2:
The patent applies preliminary action by pre-modifying T cells with c-Jun overexpression and Regnase-1/PTPN2 knockdown before antigen exposure. This preliminary genetic modification prepares the T cells to resist exhaustion mechanisms that would normally occur during continuous antigen stimulation, allowing them to maintain functionality throughout treatment.
2Productivity
If T cells are continuously stimulated by antigen, then tumor recognition and cytotoxicity are enhanced, but metabolic function changes and apoptosis increases
Solution Approach 1:
The patent alters metabolic parameters by modifying the transcriptional landscape through c-Jun overexpression. This changes how T cells regulate glucose metabolism, mitochondrial function, and energy production, allowing them to sustain high cytotoxicity without entering the metabolic dysfunction characteristic of exhaustion.
Solution Approach 2:
The patent introduces a feedback mechanism where c-Jun overexpression continuously activates transcriptional programs that counteract exhaustion signals. This creates a positive feedback loop that maintains metabolic homeostasis and prevents the metabolic collapse that would normally occur with continuous antigen stimulation.
3Measurement precision
If T cells express engineered antigen receptors, then specificity for tumor antigens is improved, but expression of inhibitory receptors increases leading to reduced effector functions
Solution Approach 1:
The patent converts the harmful effect of inhibitory receptor expression into a benefit by using c-Jun overexpression to transcriptionally reprogram T cells. This reprogramming counteracts the suppressive signals from inhibitory receptors, transforming T cells that would normally be downregulated by checkpoint molecules into sustained effector cells with enhanced tumor recognition and killing capability.
Data Source
AI summary
The present disclosure provides engineered human cells (e.g., T cells) for treatment. Also provided are expression constructs for making the engineered cells.