Inducible Chimeric Signaling Molecules for Controlled T Cell Proliferation
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Solution Overview
Problem
Current T cell therapies, particularly those using chimeric antigen receptors (CARs), face challenges such as poor in vivo expansion, toxic side effects, and variable results due to off-target toxicity and the need for lymphodepleting conditioning, which are toxic and not suitable for all patients.
Innovation Solution
The development of inducible chimeric signaling molecules (CSMs) that include an intracellular FKBP12 or FKBP12v36 multimerizing region, co-stimulatory polypeptide regions like CD27, CD28, ICOS, and 4-1BB, and a membrane-targeting region, allowing for controlled T cell activation and proliferation through a ligand inducer, reducing toxic side effects and enhancing specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric antigen receptors (CARs) are used to activate T cells for tumor targeting, then tumor-specific immune response is improved, but toxic side effects and off-target toxicity occur
Solution Approach 1:
The patent applies dynamics by making T cell activation controllable and reversible through inducible signaling molecules. The system transitions from static CAR activation to dynamic control where activation can be turned on and off based on therapeutic needs, allowing patients to receive treatment only when tumors are detected through imaging biomarkers.
Solution Approach 2:
The patent introduces an intermediary control system between the T cell and tumor target. Inducible signaling molecules act as mediators that require specific ligand binding to activate T cells, providing a controllable intermediate step that prevents uncontrolled activation and off-target toxicity while maintaining tumor-specific response capability.
2Reliability
If strong T cell activation is achieved through CAR therapy, then anti-tumor efficacy is improved, but lymphodepleting conditioning is required which is toxic and not suitable for all patients
Solution Approach 1:
The patent applies preliminary action by pre-equipping T cells with inducible signaling molecules before therapy. This allows the cells to be activated only when and where needed through ligand binding, eliminating the need for preliminary lymphodepleting conditioning while maintaining strong anti-tumor efficacy.
Solution Approach 2:
The patent changes the activation parameter from constitutive (always on) to inducible (on-demand). By using inducible signaling molecules that require ligand binding for activation, the system achieves strong T cell activation without requiring toxic lymphodepleting conditioning, as activation occurs only when the inducible system is triggered.
3Productivity
If T cell proliferation is enhanced for better in vivo expansion, then therapeutic response is improved, but variable results occur due to off-target toxicity
Solution Approach 1:
The patent uses an intermediary ligand-inducible system to control T cell proliferation. The inducible signaling molecules require specific ligand binding to activate proliferation, providing consistent and controllable expansion without off-target effects, thereby improving therapeutic response consistency.
Solution Approach 2:
The patent applies dynamics by making T cell proliferation controllable through inducible signaling. The system allows for consistent proliferation when activated by the inducible system, eliminating variability caused by uncontrolled off-target activation while maintaining enhanced in vivo expansion capability.
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 enables sustained, modulated control of T cell activation, reducing toxic side effects and improving the specificity and efficacy of T cell therapies by allowing antigen-specific targeting of tumor cells while minimizing off-target toxicity.
Implementation Method 1
an intracellular FKBP12 or FKBP12v36 variant multimerizing region, that binds to an AP1903 or AP20187 ligand, wherein the chimeric signaling molecule oligomerizes upon binding to the ligand
Data Source
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AI summary
The technology relates generally to the field of immunology and relates in part to compositions and methods for controlling the proliferation of T cells, for example, therapeutic T cells. The methods further relate to compositions and methods for inducing an immune response in a subject.