TCR-Based Chimeric Antigen Receptors for Regulated T Cell Signaling
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for cancer treatment are toxic and induce cytokine release syndrome due to unregulated surface expression and lack of key regulatory components, leading to off-tumor effects and inefficient antigen recognition.
Innovation Solution
Development of T-cell receptor-based chimeric antigen receptors (TCRs) that incorporate the endogenous TCR complex, including a 4-1BB ligand fused to a peptide binding tumor-specific antigens, to regulate signaling and reduce toxicity and off-tumor effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If monomeric CARs are used, then ease of manufacture is improved, but reliability deteriorates due to unregulated surface expression and lack of regulatory components
Solution Approach 1:
The patent merges the CAR construct with endogenous TCR complex components (CD3 chains, TCR alpha/beta chains) to create a hybrid receptor that combines the ease of CAR manufacturing with the regulatory reliability of the native TCR system. The chimeric receptor integrates signaling domains from both CAR and TCR, enabling regulated expression while maintaining manufacturability.
Solution Approach 2:
The invention creates a composite protein structure combining monomeric CAR components with multimeric TCR complex elements. This composite construct includes fused signaling domains from CD3, TCR alpha/beta chains, and CAR-derived components, achieving both ease of manufacture and reliable regulated signaling through the composite nature of the receptor complex.
2Reliability
If endogenous TCR complex is incorporated, then reliability is improved through regulated signaling, but device complexity increases
Solution Approach 1:
The patent segments the TCR complex into functional modules (CD3 chains for signaling, TCR alpha/beta chains for antigen recognition, and CAR-derived components for tumor targeting). This segmentation allows the complex system to be constructed from manageable units while maintaining the overall regulatory function and reducing the complexity burden.
Solution Approach 2:
The chimeric receptor serves multiple functions simultaneously: it provides tumor-specific targeting through CAR-derived scFv, maintains regulated signaling through TCR complex components, and enables controlled surface expression through endogenous TCR regulation mechanisms. This multi-functionality reduces the need for separate regulatory mechanisms, thereby managing complexity.
3Ease of operation
If CARs lack regulatory components, then ease of operation is improved, but object-generated harmful factors worsen due to cytokine release syndrome and off-tumor effects
Solution Approach 1:
The CAR construct utilizes the TCR complex's endogenous regulatory mechanisms to control its own surface expression and signaling activity. The chimeric receptor serves itself by harnessing the cell's existing regulatory networks, eliminating the need for external regulatory components or mechanisms while preventing harmful effects like cytokine release syndrome and off-tumor toxicity.
Data Source
AI summary
The present disclosure generally relates to chimeric antigen receptors, more specifically to chimeric antigen receptor compositions and methods for use of the same. The present disclosure also provides for nucleic acid molecules and expression vectors for making and using the chimeric antigen receptors and for co-receptor signaling using such chimeric antigen receptors. The present disclosure also provides methods of treatment using such compositions. The chimeric antigen receptors of the present disclosure interact with the endogenous T-cell receptor complex enabling physiological control of signaling and T-cell response and can be combined with ligands such as co-stimulatory ligands for further controlling and influencing T-cell activation and response.