CAR-T Cells Expressing TGFβ Modulators for Tumor Targeting

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Solution Overview

Problem

Current immunotherapy approaches, such as CAR-T cell therapies, face challenges in effectively targeting cancer cells due to the immunosuppressive tumor microenvironment, particularly high levels of TGFβ, which limit the in vivo expansion and persistence of CAR+ T cells, leading to disappointing clinical outcomes.

Innovation Solution

Development of an immune modulating system comprising engineered CAR-T cells that express a TGFβ signaling pathway modulator, enhancing the surface expression of CARs and cytolysis of cancer cells by modulating TGFβ signaling, thereby overcoming immunosuppression and improving therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cell therapy is used to target cancer cells, then tumor targeting capability is improved, but the immunosuppressive tumor microenvironment (high TGFβ levels) limits in vivo expansion and persistence of CAR+ T cells

Engineering Contradiction:

Improvetumor targeting capabilityVSAvoidin vivo expansion and persistence of CAR+ T cells

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent introduces TGFβ signaling pathway modulators (such as TGFβ-neutralizing antibodies, TGFβR antibodies, or small molecule inhibitors) as intermediary agents that block the immunosuppressive TGFβ signaling pathway in the tumor microenvironment. These modulators mediate between the CAR-T cells and the suppressive environment, preventing TGFβ from inhibiting T cell function and enabling sustained CAR-T cell persistence and anti-tumor activity

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent alters the biochemical parameters of the tumor microenvironment by inhibiting TGFβ signaling pathways. This involves changing the functional state of the microenvironment from immunosuppressive to immunopermissive, thereby enabling CAR-T cells to expand and persist effectively in vivo without being suppressed by high TGFβ levels

Inventive Principle:

Principle #35Parameter changes

2Device complexity

If TGFβ signaling is not modulated, then the system remains simple, but the immunosuppressive microenvironment prevents effective immune response

Engineering Contradiction:

Improvesystem simplicityVSAvoidimmune response efficacy

Core Design Contradiction:

Device complexityVSProductivity

Solution Approach 1:

The patent incorporates TGFβ signaling pathway modulators as intermediary components that specifically target and neutralize the immunosuppressive TGFβ pathway. This addition of a targeted intermediary agent addresses the immunosuppression problem without requiring complete system redesign, maintaining relative simplicity while significantly improving immune response efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20240226295A9Cell therapy compositions and methods for modulating TGF-b signaling

Publication Date: 2024.07.11 TAKEDA PHARMA CO LTD

AI summary

Methods of using polypeptides to modulate transforming growth factor-β (TGFβ) signaling (e.g., TGFβ receptors, antibodies or antigen-binding fragments thereof that specifically bind TGFβ or a TGFβ receptor) are provided. Compositions comprising the antibodies or fragments thereof and methods of using the same for treatment of diseases involving TGFβ activity are provided. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions comprising these antigen binding agents and fragments thereof are also disclosed. The invention also provides therapeutic methods for utilizing the TGFβ signaling modulators are provided herein.