CAR T Cells Engineered with BATF and IRF4 to Counter Exhaustion
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Solution Overview
Problem
Current CAR T cell therapies face limitations due to T-cell exhaustion, which reduces their efficacy in treating cancer and chronic infections, as they express high levels of inhibitory markers like PD-1, TIM3, and LAG3, leading to decreased proliferation and effector functions.
Innovation Solution
Engineered immune cells with increased expression and function of BATF and IRF4, which help in reducing the expression of inhibitory markers and promoting cytokine production, thereby enhancing T-cell proliferation and anti-tumor responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are engineered to target tumor antigens, then anti-tumor efficacy is improved, but T-cell exhaustion occurs leading to reduced proliferation and effector functions
Solution Approach 1:
The patent changes the molecular parameters of T cells by engineering them to express transcription factors BATF and/or IRF4. This parameter change fundamentally alters the T cell's gene expression profile, reducing exhaustion markers (PD-1, TIM3, LAG3) and enhancing proliferative capacity while maintaining anti-tumor efficacy. The parameter change transforms the T cell from an exhausted state to a sustained functional state.
2Stability of the object's composition
If CAR T cells express high levels of inhibitory markers like PD-1, TIM3, and LAG3, then immune regulation is maintained, but effector functions and proliferation are decreased
Solution Approach 1:
The patent applies parameter changes by introducing transcription factors that fundamentally alter the expression levels of inhibitory markers. BATF and IRF4 engineering shifts the T cell from a regulated but suppressed state to a state where effector functions are enhanced while immune regulation is maintained through balanced marker expression rather than high levels.
3Reliability
If CAR T cell therapy is administered for chronic infections or cancer, then therapeutic benefit is achieved, but T-cell exhaustion develops reducing sustained response
Solution Approach 1:
The patent applies preliminary action by pre-engineering T cells with transcription factors BATF and/or IRF4 before adoptive transfer. This preliminary molecular modification prevents exhaustion from developing during the therapeutic response, enabling sustained anti-tumor or anti-pathogen activity over extended periods. The T cells are prepared in advance with molecular tools that counteract exhaustion mechanisms.
Solution Approach 2:
The patent uses parameter changes to fundamentally alter the temporal dynamics of T cell function. By engineering expression of BATF and/or IRF4, the T cells transition from a transient functional state that decays due to exhaustion to a sustained functional state that maintains effector activities and proliferation capacity over long durations necessary for chronic infection or cancer control.
Data Source
AI summary
Provided herein is an engineered immune cell modified to increase expression, function, or both expression and function of any one or more of BATF or IRF4 in the immune cell, as well as methods of making and using same. The immune cell can also express a receptor or ligand that binds at least one tumor antigen or at least one antigen expressed by a pathogen. The cells can be formulated into compositions. The cells and compositions are useful as anti-cancer or ant-tumor therapies, or to treat a pathogenic infection.