Switchable CAR T Cells for Allogeneic Therapy
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Solution Overview
Problem
Conventional CAR-T cell therapies face challenges such as immune response difficulties, tumor escape variants, and immune rejection issues due to MHC mismatch, limiting their clinical applications and requiring costly and time-consuming autologous approaches.
Innovation Solution
Engineered allogeneic human T cells with reduced or eliminated surface expression of TRAC, HLA-A, and HLA class II, combined with a switchable chimeric antigen receptor, allowing for antigen-specific targeting and reduced immune rejection through genetic modifications and a reversible immune response mechanism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cell therapy is used, then antigen-specific immune response is achieved, but immune rejection due to MHC mismatch occurs
Solution Approach 1:
The patent removes MHC molecules from the surface of allogeneic T cells through genetic modification, extracting the problematic component that causes immune rejection. This allows allogeneic T cells to evade recognition by recipient immune systems while maintaining their antigen-specific killing capability through CAR expression
Solution Approach 2:
The patent creates universal allogeneic T cell products that can be used across multiple patients without requiring patient-specific customization. By eliminating MHC expression and using standardized CAR constructs, the same T cell product can be manufactured once and administered to multiple recipients, achieving both reliability in antigen targeting and avoidance of immune rejection
2Object-affected harmful factors
If autologous CAR-T cell approach is used, then immune rejection is avoided, but production time and cost increase
Solution Approach 1:
The patent performs preliminary genetic modifications to allogeneic T cells to eliminate MHC expression and equip them with universal CAR constructs before manufacturing. This preliminary preparation creates off-the-shelf products that can be rapidly produced and stored, eliminating the time-consuming process of collecting, processing, and custom-engineering patient-specific cells while pre-emptively solving the immune rejection problem
Solution Approach 2:
The patent employs allogeneic T cells that can be manufactured in large quantities, stored, and discarded after use, replacing the need for expensive and time-consuming autologous cell collection and processing. These standardized allogeneic products serve as disposable therapeutic units that eliminate both the time loss and immune rejection issues
3Reliability
If continuous CAR T cell stimulation is applied, then anti-tumor efficacy is improved, but T cell exhaustion occurs
Solution Approach 1:
The patent implements a switchable CAR system where T cell activation can be turned on and off periodically. By using inducible promoters or switchable CAR constructs, treatment can be administered in cycles with rest periods, allowing T cells to remain persistent in the body while avoiding continuous stimulation that leads to exhaustion, thereby maintaining both efficacy and duration of action
4Loss of time
If allogeneic T cells are used, then production time and cost are reduced, but immune rejection due to MHC mismatch increases
Solution Approach 1:
The patent extracts MHC molecules from the surface of allogeneic T cells through genetic modification, removing the specific component that causes immune rejection. This allows the production advantages of allogeneic cells to be realized while eliminating the disadvantage of MHC-mediated rejection, enabling rapid manufacturing without the harmful immune response
Data Source
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AI summary
The present invention relates to an engineered human T cell comprising a switchable chimeric antigen cell surface receptor, a pharmaceutical composition comprising the engineered human T cell, a kit comprising the engineered human T cell and a targeting module and a method for generating the engineered human T cell.