Gamma-Delta CAR Immune Cells With Polycistronic Co-Expression
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Solution Overview
Problem
Existing immune cell therapies face challenges including immune cell mediated toxicities, off-target effects, and tumor escape, and tumor escape, which limit the success of the field.
Innovation Solution
A polycistronic construct used to induce co-expression of a chimeric antigen receptor (CAR) together with γδ-TCR monomers, which greatly enhances per-cell expression of the CAR, particularly when the CAR is positioned between the γδ-TCR monomers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cells are modified with engineered anti-tumor activity, then cancer targeting capability is improved, but immune cell mediated toxicities and off-target effects increase
Solution Approach 1:
The patent segments the immune cell modification into distinct functional components: a CAR expressing T cell receptor (TCR) for tumor targeting, a heterodimeric γδ T cell receptor (γδ-TCR) for specificity control, and a chimeric antigen receptor (CAR) for antigen recognition. This modular segmentation allows each component to be optimized independently to reduce toxicities while maintaining cancer targeting capability.
Solution Approach 2:
The patent introduces an intermediary mechanism through the heterodimeric γδ-TCR that acts as a mediator between the CAR and the tumor target. This intermediary receptor complex provides an additional layer of specificity and control, reducing off-target effects while maintaining the anti-tumor activity of the CAR.
2Productivity
If CAR expression is enhanced in immune cells, then tumor targeting efficiency is improved, but manufacturing complexity increases
Solution Approach 1:
The patent merges the expression of multiple receptors (CAR and γδ-TCR monomers) into a single polycistronic construct that is co-expressed from one promoter. This combining approach achieves enhanced CAR expression and tumor targeting efficiency while simplifying the manufacturing process compared to using separate expression constructs for each receptor component.
Solution Approach 2:
The polycistronic construct serves multiple functions simultaneously: it expresses the CAR for antigen recognition, expresses γδ-TCR monomers for heterodimer formation, and provides coordinated regulation through a single promoter. This multi-functionality reduces manufacturing complexity by eliminating the need for multiple separate expression systems.
3Reliability
If multiple receptors are co-expressed in immune cells, then tumor specificity is improved, but expression control becomes more difficult
Solution Approach 1:
The patent combines the expression control of multiple receptors under a single promoter system. The polycistronic construct ensures that the CAR and γδ-TCR monomers are co-expressed in a coordinated manner, maintaining tumor specificity while simplifying expression control compared to using separate promoters for each receptor.
Solution Approach 2:
The patent uses a standardized promoter sequence that can be copied and applied to different CAR and γδ-TCR construct configurations. This modular copying approach maintains consistent expression control across different receptor combinations while preserving tumor specificity.
Data Source
AI summary
Modified immune cells expressing a heterodimeric gamma-delta T cell receptor (TCR) and a chimeric antigen receptor (CAR) are described. The disclosed modified immune cells enhance expression of CARs. Also disclosed are compositions and methods for making such cells, and use of such cells in treating disease.