Regulatable Destabilization Domain Modulates CAR Surface Expression

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Solution Overview

Problem

T cell exhaustion, characterized by dysfunction and loss of effector function in chronic infections or cancer, occurs due to persistent antigen exposure leading to continuous TCR signaling, which existing methods have been unable to effectively prevent or reverse.

Innovation Solution

Modulation of CAR surface expression in CAR T cells through the use of a regulatable destabilization domain (RDD) such as FKBP or DHFR, allowing for transient inhibition of TCR signaling by stabilizing or destabilizing the CAR protein, thereby preventing tonic signaling and restoring T cell function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If CAR T cells continuously express CAR to maintain anti-tumor activity, then tumor killing capacity is improved, but T cell exhaustion and dysfunction occur

Engineering Contradiction:

Improveanti-tumor activityVSAvoidT cell function

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies dynamics by making CAR expression on T cells adjustable rather than fixed. Through the regulatable destabilization domain (RDD), CAR expression can be dynamically increased to enhance anti-tumor activity when needed, and decreased to prevent exhaustion and restore T cell function, resolving the contradiction between maintaining productivity and preserving reliability

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes the parameter of CAR surface expression levels on T cells. By using small molecule ligands to modulate the stability of the CAR-RDD fusion protein, the system can alter CAR expression parameters to optimize both tumor killing capacity and prevent exhaustion, allowing the system to adapt between high productivity and high reliability states

Inventive Principle:

Principle #35Parameter changes

2Productivity

If TCR signaling is continuously activated to maintain T cell responsiveness, then effector function is improved, but T cell exhaustion is worsened

Engineering Contradiction:

Improveeffector functionVSAvoidT cell functionality

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent implements periodic action by enabling intermittent rather than continuous TCR signaling. The regulatable CAR expression allows the system to alternate between periods of high signaling (for effector function) and low signaling (for recovery), preventing the continuous activation that leads to exhaustion while maintaining overall productivity

Inventive Principle:

Principle #19Periodic action

3Productivity

If CAR expression is increased to enhance T cell activity, then anti-tumor efficacy is improved, but T cell exhaustion is worsened

Engineering Contradiction:

ImproveT cell activityVSAvoidT cell exhaustion

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces an intermediary mechanism (the regulatable destabilization domain with small molecule ligands) that mediates between CAR expression levels and T cell exhaustion. This intermediary allows precise control over CAR stability and surface expression, enabling the system to achieve high activity when needed while preventing exhaustion through controlled reduction of expression

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach effectively reverses T cell exhaustion by controlling CAR T cell signaling, enhancing their functionality and maintaining their activity against cancer or infectious diseases, even under conditions where unmodified CAR T cells would become dysfunctional.

Implementation Method 1

the modified CAR protein is shielded from degradation and the CAR construct comprising an RDD is stably expressed

Methodology Applied

Scientific EffectProteasomal degradation:

Implementation Method 2

By adding a ligand such as a small molecule or drug (e.g., Shield-1 or trimethoprim (TMP)), the modified CAR protein is shielded from degradation

Methodology Applied

Scientific EffectLigand binding:

Data Source

PatentUS20240293461A1Methods of Treating T Cell Exhaustion by Inhibiting or Modulating T Cell Receptor Signaling

Publication Date: 2024.09.05 THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV

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 chimeric antigen receptor (CAR) T cells that are modified to maintain functionality under conditions in which unmodified CAR T cells display exhaustion. Compositions and methods disclosed herein find use in inhibiting or reversing CAR T cell exhaustion (e.g., by modulating CAR surface expression) thereby enhancing CAR T cell function. Compositions and methods of the invention find use in both clinical and research settings, for example, within the fields of biology, immunology, medicine, and oncology.