CAR Polypeptide NS3 Protease Switching for Reversible T Cell Control
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Solution Overview
Problem
Current CAR T cell therapies face challenges with cytokine release syndrome due to T cell overactivity, leading to organ failure or death, and existing suicide-switches are irreversible and costly, lacking FDA-approved molecules for safe control.
Innovation Solution
Development of drug-inducible and drug-repressible CAR polypeptides using the hepatitis C virus NS3 protease, allowing reversible control over T cell activity with FDA-approved protease inhibitors, enabling customizable and safe adoptive T cell therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If drug-inducible suicide switches are used to control overactive T cells, then T cell activity can be regulated, but the control is irreversible and cells cannot be reused
Solution Approach 1:
The patent implements a dynamic control system where the CAR polypeptide's activity can be reversibly activated or inactivated through protease inhibitor treatment. The system transitions between active and inactive states based on the presence or absence of the inhibitor, allowing flexible regulation without irreversible cell death. This enables repeated use of the same T cells for multiple treatment cycles.
Solution Approach 2:
The invention changes the control parameter from irreversible genetic modification to reversible biochemical inhibition. By using protease inhibitors that temporarily block protease activity, the system achieves reversible control where the CAR polypeptide can be switched on and off without permanent alteration to the T cells, maintaining their viability and reusability.
2Reliability
If existing suicide-switch mechanisms are used, then T cell overactivity can be controlled, but FDA-approved molecules for safe control are unavailable
Solution Approach 1:
The patent utilizes the hepatitis C virus NS3 protease, which is targeted by multiple existing FDA-approved protease inhibitors used for hepatitis C treatment. This approach leverages already-approved, safe molecules for a new indication (CAR T cell control), eliminating the need to develop and approve new control agents from scratch.
Solution Approach 2:
The invention introduces an intermediary protease (HCV NS3 protease) that serves as a controllable switch mechanism. This intermediary can be inhibited by FDA-approved molecules, providing a safe and regulated way to control CAR T cell activity without requiring direct modification of the CAR structure or development of new pharmaceutical agents.
3Productivity
If T cell activity is increased to enhance anti-cancer effect, then therapy effectiveness improves, but cytokine release syndrome and organ failure risk increase
Solution Approach 1:
The patent implements a feedback control mechanism where protease inhibitors can be administered to suppress CAR T cell activity when cytokine release syndrome symptoms appear. The system monitors the therapeutic response and adjusts T cell activity levels accordingly, allowing the treatment to be paused or reduced when harmful effects emerge, then resumed when safe.
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
Provides flexible and safe control over T cell activity, reducing the risk of cytokine storms and enabling reusable CAR T cells with a favorable toxicity profile.
Implementation Method 1
the activity of the CAR polypeptide can be controlled by a protease inhibitor. The CAR polypeptides also comprise additional components such that presence of a specific protease inhibitor either activates or inactivates the CAR polypeptide
Data Source
AI summary
The technology described herein is directed to CAR polypeptides and systems comprising repressible proteases. In combination with a specific protease inhibitor, the activity of said CAR polypeptides and systems and cells comprising them can be modulated. Also described herein are methods of using said CAR polypeptides and systems, for example to treat various diseases and disorders.