Engineered CAR Compositions With Mixed-Vector Activity Modulation

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Solution Overview

Problem

Heterogeneity in tumor cells and microenvironments poses challenges for effective CAR-T cell therapy, including variable antigen expression and resistance to treatment, poor persistence, and difficulty in engrafting within solid tumors.

Innovation Solution

A combinatorial approach using a mixture of viral vectors to transduce cells with multiple CARs and activity modulators, allowing for flexibility in adapting to tumor heterogeneity and enhancing persistence and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If a single CAR targets a specific antigen, then CAR-T cell specificity is improved, but effectiveness against heterogeneous tumor populations deteriorates

Engineering Contradiction:

ImproveCAR-T cell specificityVSAvoideffectiveness against heterogeneous tumor populations

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent segments the CAR-T cell therapy into multiple CAR types, each targeting different antigens or epitopes. This segmentation allows the therapy to address multiple tumor targets simultaneously, overcoming the limitation of single-CAR specificity while maintaining precision against each individual target.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates multi-functional CAR-T cells that can recognize and respond to multiple tumor antigens through a single CAR construct. This multi-functionality enables the CAR-T cells to effectively target heterogeneous tumor populations while maintaining specificity for each antigen, resolving the contradiction between precision and broad effectiveness.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Power

If CAR-T cells are designed for high antigen recognition, then killing capacity is improved, but persistence in heterogeneous tumor microenvironments deteriorates

Engineering Contradiction:

Improvekilling capacityVSAvoidpersistence in tumor microenvironment

Core Design Contradiction:

PowerVSDuration of action of stationary object

Solution Approach 1:

The patent modifies parameters of the CAR-T cell therapy by introducing costimulatory domains and cytokine secretion capabilities. These parameter changes enhance both the killing capacity through improved antigen recognition and persistence through enhanced survival signals, allowing simultaneous optimization of both functions.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite CAR-T cell constructs that combine multiple functional elements: antigen recognition domains, costimulatory signals, and cytokine production capabilities. This composite approach enables the CAR-T cells to achieve both high killing capacity and prolonged persistence in the tumor microenvironment.

Inventive Principle:

Principle #40Composite materials

3Power

If CAR-T cells target highly expressed antigens, then initial tumor killing is improved, but resistance to treatment deteriorates

Engineering Contradiction:

Improveinitial tumor killingVSAvoidresistance to treatment

Core Design Contradiction:

PowerVSReliability

Solution Approach 1:

The patent segments the antigen targeting into multiple different antigens or epitopes within the CAR-T cell population. This segmentation ensures that even if tumor cells develop resistance to one antigen target, other CAR-T cells can continue to recognize and kill through alternative targets, preventing treatment failure.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent converts the potential harm of antigen loss or downregulation (a common resistance mechanism) into a benefit by designing CAR-T cells with multiple antigen specificities. When tumor cells attempt to escape through antigen loss, the multi-specific CAR-T cells can switch targets, transforming the resistance mechanism into a non-issue.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

4Adaptability or versatility

If CAR-T cells are engineered for multi-specificity, then adaptability to tumor heterogeneity is improved, but device complexity deteriorates

Engineering Contradiction:

Improveadaptability to tumor heterogeneityVSAvoidCAR construct complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent merges multiple antigen recognition specificities into a single CAR construct through the use of multiple Ig domains or TCR elements within one receptor. This merging approach achieves multi-specificity and adaptability to tumor heterogeneity while avoiding the complexity of multiple separate CAR constructs or cell lines.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250296976A1Compositions and methods comprising engineered chimeric antigen receptor and modulator of car

Publication Date: 2025.09.25 AUTOLUS LIMIED

AI summary

There is provided method for making a cell composition which comprises step of transducing a population of cells with a mixture of at least two viral vectors, wherein at least one vector comprises a nucleic acid sequence which encodes a chimeric antigen receptor (CAR); and wherein at least one vector comprises a nucleic acid encoding an activity modulator which modulates the activity of the CAR, of a cell expressing the CAR, or of a target cell. There is also provided a cell composition made by such a method and its use in the treatment of diseases such as cancer.