Parallel CAR T-Cell Receptors for Sustained Co-Stimulation
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Solution Overview
Problem
Existing chimeric antigen receptors (CARs) for cancer immunotherapy, particularly third generation CARs, show marginal improvements over second generation configurations, and transformed T-cells lose effector functions rapidly upon repeated stimulation due to sub-optimal co-stimulation, leading to anergy and reduced longevity.
Innovation Solution
A combination of distinct constructs, each with a signaling region and a co-stimulatory region, is used to create parallel chimeric activating receptors (pCARs) that maintain cytotoxic potency and cytokine release over multiple stimulations by arranging co-stimulatory modules adjacent to the plasma membrane without steric interference.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If third generation CARs combine multiple signaling domains (CD28+4-1BB+CD3z) to augment potency, then T-cell activation is enhanced, but the improvement over second generation configurations is only marginal
Solution Approach 1:
The patent divides the co-stimulatory signaling function into two separate CAR constructs rather than combining multiple domains in one construct. Each CAR expresses a single co-stimulatory domain (CD28 or 4-1BB) fused to CD3zeta, creating functionally distinct but complementary receptors that together provide enhanced activation without the complexity of multi-domain fusion proteins
Solution Approach 2:
The patent transitions from a single-dimension approach (one CAR with multiple domains) to a multi-dimensional approach (multiple CARs working in parallel). By expressing two separate CARs with different co-stimulatory domains, the system achieves enhanced potency through combinatorial signaling rather than through increasing the complexity of a single receptor structure
2Reliability
If T-cells are transformed with multiple constructs to provide co-stimulation, then tumour sensing effect is enhanced, but T-cells lose effector functions rapidly upon repeated stimulation due to sub-optimal co-stimulation
Solution Approach 1:
The patent optimizes the co-stimulatory signaling parameters by selecting specific co-stimulatory domains (CD28 and 4-1BB) with different kinetic and signaling properties. This parameter optimization ensures that T-cells receive appropriate co-stimulation signals that maintain effector functions over multiple stimulations, preventing anergy while preserving tumour sensing specificity
Solution Approach 2:
The patent creates a composite T-cell system that expresses multiple CAR constructs with different co-stimulatory domains. This composite approach combines the advantages of different signaling pathways, where CD28 provides strong initial activation and 4-1BB sustains prolonged effector function, thereby maintaining T-cell potency over repeated antigen exposures
3Power
If co-stimulatory modules are placed upstream of CD3z in series alignment, then signaling is provided, but steric interference may occur and marginal improvement is achieved
Solution Approach 1:
The patent segments the signaling architecture by placing each co-stimulatory domain in a separate construct rather than aligning multiple domains in series within one construct. This segmentation eliminates steric interference between domains while maintaining effective signal transduction, as each CAR independently traffics and signals without physical obstruction from other domains
Data Source
AI summary
An immunoresponsive cell, such as a T-cell expressinga 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; anda 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.