PEG Receptor-Engineered CAR-T Cells for Controlled Activation

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Solution Overview

Problem

Current CAR-T cell therapies for solid tumors face challenges in activating and expanding cells due to insufficient target antigen abundance and cytokine availability, leading to suboptimal efficacy and increased cytokine release syndrome, necessitating controlled cellular expansion and targeted delivery of activation signals.

Innovation Solution

Genetically engineered induced pluripotent stem cells (iPSCs) expressing polyethylene glycol (PEG) receptors, which form chimeric antigen receptors (CARs) and cytokine receptors, are transduced to respond to PEG-based drugs for controlled activation and expansion, allowing for targeted and regulated cell therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cells are activated through CAR binding to target antigens, then cell activation occurs, but insufficient activation signals are delivered due to low target antigen abundance on solid tumor cells

Engineering Contradiction:

Improvecell activation reliabilityVSAvoidactivation signal quantity

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent introduces PEG as an intermediary substance that bridges the gap between CAR-T cells and solid tumor cells. PEG is administered systemically and binds to PEG receptors on tumor cells, providing abundant binding sites that amplify activation signals to CAR-T cells, thereby overcoming the limitation of low target antigen abundance on solid tumor surfaces

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the activation parameter from direct CAR-antigen binding to PEG-receptor mediated activation. By administering exogenous PEG, the system transforms the activation mechanism into a two-step process: PEG binds to PEG receptors on tumor cells, then CAR-T cells recognize PEG through PEG-specific CARs, amplifying the activation signal through PEG multimerization

Inventive Principle:

Principle #35Parameter changes

2Productivity

If cytokine signals are provided to support cell expansion, then proliferative response increases, but cytokine release syndrome and toxicities increase

Engineering Contradiction:

Improvecell expansion rateVSAvoidcytokine release syndrome

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent uses PEG as an intermediary that delivers cytokine signals in a controlled manner. PEG binds to PEG-receptor-CAR complexes on activated CAR-T cells, providing a platform for cytokine presentation. This intermediary mechanism allows cytokine signals to be delivered selectively to activated cells, enhancing expansion while controlling systemic cytokine release

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent establishes a feedback loop where PEG administration triggers CAR-T cell activation and expansion, which in turn increases PEG receptor occupancy and amplifies cytokine signaling. This feedback mechanism ensures that cytokine signals are provided proportionally to the level of cell activation, preventing excessive cytokine release syndrome

Inventive Principle:

Principle #23Feedback

3Reliability

If lymphodepleting chemotherapy is used to increase cytokine availability, then cell activation is enhanced, but treatment complexity and toxicity increase

Engineering Contradiction:

Improvecell activationVSAvoidtreatment regimen complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts the cytokine delivery function from the complex lymphodepleting chemotherapy regimen. By using PEG as a standalone activator that provides both target engagement and cytokine signal delivery, the system separates the activation function from the cytotoxic chemotherapy, simplifying the treatment paradigm while maintaining activation reliability

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent makes PEG a multi-functional agent that simultaneously: (1) serves as a target engagement molecule for CAR-T cells, (2) provides abundant binding sites for activation, (3) delivers cytokine signals for expansion, and (4) controls activation timing and magnitude. This universal approach replaces multiple separate treatment components with a single PEG-based system

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 precise control over CAR-T cell activation and expansion, enhancing therapeutic efficacy while reducing toxicities associated with cytokine release syndrome, by leveraging PEG receptors for targeted signaling and expansion.

Implementation Method 1

Genetically engineered induced pluripotent stem cells (iPSCs) expressing polyethylene glycol (PEG) receptors, which form chimeric antigen receptors (CARs) and cytokine receivers

Methodology Applied

Scientific EffectReceptor binding:

Implementation Method 2

enables precise control over CAR-T cell activation and expansion, enhancing therapeutic efficacy while reducing toxicities associated with cytokine release syndrome

Methodology Applied

Scientific EffectCellular proliferation signaling:

Data Source

PatentUS20230381317A1Methods for controlled activation and/or expansion of genetically engineered cells using polyethylene glycol (PEG) receptors

Publication Date: 2023.11.30 CENTURY THERAPEUTICS INC

AI summary

Provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing a polyethylene glycol (PEG) receptors and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.