Glucocorticoid Signaling Modulation for T Cell Dysfunction
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Solution Overview
Problem
Current therapies fail to effectively address T cell dysfunction in the tumor microenvironment, leading to suppressed anti-tumor immune responses, as the mechanisms promoting T cell exhaustion are not fully understood, and there is a need for improved markers and methods to modulate immune responses.
Innovation Solution
Modulating glucocorticoid and IL-27 signaling in T cells using agents that either enhance or reduce these pathways to alter T cell dysfunction, including the use of glucocorticoid agonists/antagonists and IL-27 agonists/antagonists to target specific gene signatures and receptors, thereby modifying the functional state of T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If glucocorticoid signaling is enhanced to suppress immune responses, then immune suppression increases, but anti-tumor immune responses are further inhibited
Solution Approach 1:
The patent applies local quality by differentiating between global immune suppression and localized anti-tumor immunity. It targets glucocorticoid signaling specifically in the tumor microenvironment through localized delivery methods (e.g., tumor-targeting nanoparticles, intra-tumoral injection) while preserving systemic immune competence. This allows suppression of harmful immune responses locally at the tumor site without compromising overall anti-tumor immunity elsewhere in the body.
Solution Approach 2:
The patent uses intermediary molecules such as glucocorticoid receptor modulators (GRMs) that selectively bind to GR in tumor-associated immune cells rather than causing broad systemic immunosuppression. These intermediaries mediate the effect of glucocorticoids specifically on pathological immune responses while sparing protective anti-tumor immunity through selective cell-type targeting or conditional activation.
2Reliability
If glucocorticoid signaling is reduced to enhance anti-tumor immune responses, then anti-tumor immunity improves, but harmful immune suppression decreases
Solution Approach 1:
The patent employs periodic or pulsatile administration of glucocorticoid modulators to temporarily suppress harmful immune responses during specific phases of immune activation. By timing the intervention to coincide with periods of pathological immune suppression rather than continuous suppression, the treatment allows anti-tumor immunity to recover and function between pulses, thereby resolving the contradiction between reducing harm and maintaining protection.
Solution Approach 2:
The patent utilizes dynamic regulation of glucocorticoid signaling through inducible or responsive systems that adjust the level of signaling inhibition based on real-time immune status. This dynamic approach allows the system to suppress glucocorticoid signaling when harmful immune suppression is detected while allowing normal signaling to persist when anti-tumor immunity is active, thereby adapting to changing immune conditions rather than applying static suppression.
3Measurement precision
If T cell dysfunction is increased to model disease states in vitro, then disease modeling accuracy improves, but therapeutic applicability decreases
Solution Approach 1:
The patent applies partial action by inducing T cell dysfunction in vitro to a controlled extent that mimics key pathological features without achieving complete exhaustion. This partial dysfunction state retains enough T cell viability and responsiveness to allow subsequent therapeutic intervention and recovery, enabling both accurate disease modeling and subsequent therapeutic testing in the same system.
Solution Approach 2:
The patent uses preliminary in vitro induction of T cell dysfunction as a preparatory step that creates a more physiologically relevant starting model for subsequent in vivo or clinical studies. By pre-establishing dysfunction markers and phenotypes in culture, the system better replicates the pathological state that will be encountered in actual disease, thereby improving the predictive value and applicability of subsequent therapeutic interventions without permanently compromising cell functionality.
Data Source
AI summary
The subject matter disclosed herein is generally directed to modulating T cell dysfunctional and effector states by modulating glucocorticoid and IL-27 signaling. The invention further relates to modulating immune states, such as CD8 T cell immune states, in vivo, ex vivo and in vitro. The invention further relates to diagnostic and screening methods.