Parallel CAR T Cell Architecture to Limit Exhaustion

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Solution Overview

Problem

Existing chimeric antigen receptor (CAR)-T cell therapies for cancer treatment, particularly third-generation configurations, show limited efficacy due to T cell exhaustion and a need for broader antigen target combinations.

Innovation Solution

Development of parallel CAR (pCAR) constructs that express a second-generation CAR and a chimeric co-stimulatory receptor (CCR) in parallel, targeting antigens like CD19 or other B cell lineage markers, such as CD20, CD22, CD23, CD79a, and CD79b, to enhance T cell activation and resistance to exhaustion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If third-generation CAR configurations are used to enhance T cell activation, then co-stimulatory signaling is improved, but T cell exhaustion occurs and efficacy is limited

Engineering Contradiction:

ImproveT cell activation efficacyVSAvoidT cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent divides the co-stimulatory signaling function into two separate constructs: a second-generation CAR that provides antigen-specific signaling and one co-stimulatory signal, and a separate CCR that provides an additional co-stimulatory signal without antigen binding. This segmentation prevents the exhaustion associated with third-generation CARs while maintaining enhanced activation through the distributed co-stimulatory signals from both constructs working in parallel.

Inventive Principle:

Principle #1Segmentation

2Power

If multiple co-stimulatory domains are combined in a single CAR construct, then T cell activation is enhanced, but the system becomes more complex and less effective

Engineering Contradiction:

ImproveT cell activation potencyVSAvoidCAR construct complexity

Core Design Contradiction:

PowerVSDevice complexity

Solution Approach 1:

Instead of combining multiple co-stimulatory domains in a single CAR construct, the patent segments the functionality into a second-generation CAR (with one co-stimulatory domain) and a separate CCR (with another co-stimulatory domain). This reduces the complexity of each individual construct while achieving enhanced activation through the combined action of both constructs expressed in the same T cell.

Inventive Principle:

Principle #1Segmentation

3Adaptability or versatility

If parallel CAR constructs targeting multiple B cell antigens are used, then therapeutic versatility is improved, but manufacturing complexity increases

Engineering Contradiction:

Improveantigen target coverageVSAvoidcell therapy production

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent creates a universal platform where T cells are engineered to express both a second-generation CAR and a CCR. The CAR component can be configured to target different B cell antigens (CD19, CD20, CD22, etc.) while the CCR provides a consistent additional co-stimulatory function. This multi-functional design allows the same basic construct architecture to be applied across multiple antigen targets, improving versatility without proportionally increasing manufacturing complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS12534507B2B cell targeted parallel car (pCAR) therapeutic agents

Publication Date: 2026.01.27 KINGS COLLEGE LONDON

AI summary

Provided herein are immuno-responsive cells expressing a B cell targeting pCAR comprising a 2nd generation chimeric antigen receptor (CAR) and a chimeric co-stimulatory receptor (CCR). Also provided herein are methods of preparing the immuno-responsive cells and methods of directing T cell mediated immune response using the immuno-responsive cells.