Parallel CAR T-Cell Receptors for Sustained Co-Stimulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing chimeric antigen receptors (CARs) for cancer immunotherapy, particularly third generation CARs, show marginal improvements over second generation configurations and fail to maintain T-cell effector functions and cytokine production upon repeated stimulation, leading to rapid loss of potency and undesired anergy.
Innovation Solution
A combination of distinct constructs, each with a signaling region and a co-stimulatory region, is arranged to ensure both regions are adjacent to the plasma membrane and spaced apart, forming 'parallel chimeric activating receptors (pCARs) to enhance T-cell proliferation, cytotoxic potency, and IL-2 release during repeated antigen stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Force
If third generation CARs combine multiple signaling domains in series, then co-stimulatory signal strength is improved, but T-cell effector function longevity deteriorates due to sub-optimal signaling and rapid anergy onset
Solution Approach 1:
The invention divides the co-stimulatory signaling function into separate, parallel constructs rather than combining multiple domains in series. Each construct contains a single co-stimulatory domain (CD28 or 4-1BB) fused to the CAR structure, allowing independent signaling pathways to operate simultaneously without steric interference, thereby maintaining sustained T-cell activation and preventing rapid anergy
Solution Approach 2:
The invention transitions from a linear arrangement of signaling domains (series configuration in third generation CARs) to a parallel arrangement where multiple co-stimulatory constructs operate simultaneously. This dimensional shift from series to parallel architecture enables independent signaling pathways to function concurrently, providing sustained co-stimulation without the steric constraints that limit series configurations
2Power
If multiple co-stimulatory domains are combined in a single CAR construct, then signaling potency is improved, but steric issues arise that limit proper signaling and T-cell activation
Solution Approach 1:
The invention segments the co-stimulatory signaling function into separate CAR constructs, each containing a single co-stimulatory domain. This segmentation eliminates steric interference between multiple domains within a single construct while maintaining high signaling potency through parallel activation of multiple independent signaling pathways
Solution Approach 2:
The invention uses separate CAR constructs as intermediaries to deliver co-stimulatory signals. Each construct acts as an independent mediator that can bind to its specific ligand and transmit signaling without physical interference from other co-stimulatory domains, thereby achieving high signaling potency without steric constraints
3Productivity
If T-cells are repeatedly stimulated by antigen-expressing tumour cells, then tumouricidal activity is improved, but effector functions are lost due to sub-optimal co-stimulation and anergy
Solution Approach 1:
The invention ensures continuous co-stimulatory signaling through parallel CAR constructs that simultaneously engage their respective ligands on tumour cells. This continuous dual co-stimulation prevents the onset of anergy during repeated stimulations, allowing T-cells to maintain effector functions and tumouricidal activity over multiple cycles of antigen exposure
Solution Approach 2:
The invention changes the signaling parameter configuration from series to parallel arrangement of co-stimulatory domains. This parameter change enables sustained co-stimulatory signal delivery during repeated antigen stimulations, preventing anergy and maintaining reliable effector function retention while preserving high tumouricidal activity
Data Source
AI summary
An immunoresponsive cell, such as a T-cell expressing(i) a second generation chimeric antigen receptor comprising:(a) a signalling region;(b) a co-stimulatory signalling region;(c) a transmembrane domain; and(d) a binding element that specifically interacts with a first epitope on a target antigen; and(ii) a chimeric costimulatory receptor comprising(e) a co-stimulatory signalling region which is different to that of (b);(f) a transmembrane domain; andg) a binding element that specifically interacts with a second epitope on a target antigen.This arrangement is referred to as parallel chimeric activating receptors (pCAR). Cells of this type are useful in therapy, and kits and methods for using them as well as methods for preparing them are described and claimed.