Chimeric Receptor Endodomain for Solid Tumor CAR T-Cell Persistence
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Solution Overview
Problem
Existing chimeric antigen receptors (CARs) face challenges in effectively treating solid tumors due to the hostile immunosuppressive microenvironment, with limitations in CAR T-cell persistence and activity, including systemic toxicity from cytokine administration and uncontrolled proliferation.
Innovation Solution
Development of a chimeric receptor (CR) that combines a cytokine receptor endodomain and intracellular T-cell signaling domain, enhancing activation and proliferation by providing both cytokine-type and T cell receptor-type signals, enabling better engraftment and expansion in hostile tumor microenvironments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokines are administered systemically to enhance CAR T-cell persistence and activity, then T-cell function is improved, but toxicity occurs
Solution Approach 1:
The patent introduces a cytokine receptor endodomain as an intermediary component within the chimeric receptor structure. This allows the T-cell to respond to cytokine signals locally at the antigen binding site rather than requiring systemic cytokine administration, thereby achieving enhanced T-cell persistence and activity without the associated toxicity of systemic cytokine therapy
Solution Approach 2:
The chimeric receptor enables the T-cell to self-stimulate through the inclusion of cytokine receptor endodomains that can bind to cytokines or cytokine-like structures. This self-service mechanism allows the T-cell to maintain its own persistence and activity signals without external cytokine administration, avoiding the toxicity associated with systemic cytokine therapy
2Reliability
If cytokines are constitutively produced by CAR T-cells to enhance persistence, then T-cell activity is improved, but uncontrolled proliferation and transformation occur
Solution Approach 1:
The patent segments the cytokine signaling function from the cytokine production function by incorporating cytokine receptor endodomains into the chimeric receptor structure. This allows the T-cell to receive cytokine signals without constitutively producing cytokines, thereby maintaining persistence while avoiding uncontrolled proliferation and transformation associated with constitutive cytokine production
Solution Approach 2:
The cytokine receptor endodomain acts as an intermediary that allows the T-cell to respond to cytokine signals without requiring constitutive cytokine production. This mediator approach enables controlled T-cell persistence through external or localized cytokine signals rather than uncontrolled internal production
3Measurement precision
If conventional CAR structures are used to treat solid tumors, then antigen recognition is achieved, but the hostile immunosuppressive microenvironment prevents effective T-cell function
Solution Approach 1:
The patent merges multiple functional domains into a single chimeric receptor structure: the antigen recognition domain (scFv), the transmembrane domain, the T-cell signaling domain (CD3 zeta), and the cytokine receptor endodomain. This combination allows the T-cell to simultaneously recognize tumor antigens and receive enhanced activation and persistence signals, overcoming the suppressive tumor microenvironment while maintaining precise antigen recognition
Solution Approach 2:
The chimeric receptor functions as a composite molecular structure combining different functional elements from antibody (scFv), T-cell receptor (CD3 zeta), and cytokine receptor (cytokine receptor endodomain) systems. This composite structure integrates antigen recognition, activation signaling, and persistence signaling capabilities, enabling effective T-cell function in the hostile solid tumor microenvironment
Data Source
AI summary
The present invention provides a chimeric receptor which comprises: a ligand-binding exodomain; and an endodomain which comprises: (i) a cytokine receptor endodomain; and (ii) an intracellular T cell signalling domain.