Logic AND Gate CAR T Cells for Tumor Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current T cell therapies, such as those using chimeric antigen receptors (CARs), face challenges in selectively targeting cancer cells while avoiding healthy cells, particularly due to antigen loss escape variants and shared antigen expression between cancer and healthy tissues, leading to potential off-target effects and reduced therapeutic efficacy.
Innovation Solution
The development of immune cells engineered with synthetic biology principles, specifically a 'logic AND GATE' system that requires the combination of at least two input signals for activation, utilizing chimeric antigen receptors with transmitter domains that only activate upon simultaneous recognition of specific tumor cell ligands, ensuring targeted immune cell response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR T cell therapy is used to target cancer cells, then T cell activation and tumor killing occur, but off-target effects happen due to recognition of shared antigens on healthy cells
Solution Approach 1:
The patent segments the T cell activation process by dividing the signaling domains into multiple independent components (first signaling domain from CD3zeta, second signaling domain from co-stimulatory molecules) that must be co-assembled with specific transcription factors to achieve activation. This segmentation ensures that single antigen recognition is insufficient for activation, resolving the contradiction between tumor targeting and off-target effects.
Solution Approach 2:
The patent changes the activation threshold parameter by requiring simultaneous presence of multiple signaling inputs (antigen recognition plus co-stimulatory signals) rather than single signal activation. This parameter change raises the activation threshold to distinguish tumor cells from healthy cells expressing the same antigen, thereby reducing off-target effects while maintaining tumor killing efficacy.
2Measurement precision
If T cells are engineered with high activation sensitivity to detect tumor antigens, then tumor detection capability improves, but specificity decreases leading to activation against healthy cells
Solution Approach 1:
The patent introduces intermediary transcription factors (such as NFAT, NF-kB, AP-1) that act as mediators between antigen recognition and T cell activation. These intermediaries require specific combinatorial signaling inputs to become activated, thereby maintaining high sensitivity for tumor antigen detection while ensuring activation specificity by requiring multiple correlated signals that are simultaneously present only on tumor cells.
3Productivity
If conventional CAR design with single antigen targeting is used, then T cell expansion is achieved, but antigen loss escape variants can grow unchecked
Solution Approach 1:
The patent applies multi-functionality by engineering T cells to recognize and respond to multiple tumor-associated antigens simultaneously through the presence of multiple signaling domains and transcription factors. This multi-functional design ensures that T cells can target cancer cells through multiple antigen pathways, preventing escape by antigen loss variants while maintaining robust T cell expansion and therapeutic efficacy.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention relates to a method to engineer immune cell for immunotherapy. In particular said immune cells are engineered with chimeric antigen receptors, which be activated by the combination of hypoxia and ligand extracellular binding as input signals. The invention also relates to new designed chimeric antigen receptors which are able to redirect immune cell specificity and reactivity toward a selected target exploiting the ligand-binding domain properties and the hypoxia condition. The present invention also relates to cells obtained by the present method, in particular T-cells, comprising said chimeric antigen receptors for use in cancer treatments.