Modified T Cells With TCR Knockout for Allogeneic Persistence
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Solution Overview
Problem
Current adoptive T cell therapy faces challenges with autologous cells, requiring specialized personnel and facilities, and allogeneic cells face immune reactions leading to low persistence and graft-versus-host effects.
Innovation Solution
Modified T lymphocytes with reduced or eliminated T Cell Receptor (TCR) expression, such as through gene mutations or deletions, and inclusion of heterologous proteins to evade immune attack, along with chimeric antigen receptors (CARs) for targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous T cells are used in adoptive therapy, then cell persistence and lack of rejection are improved, but specialized personnel and facilities are required and processing time is extended
Solution Approach 1:
The patent uses allogeneic donor T cells as copies of autologous therapy cells, which can be stored and processed more easily. These donor cells are genetically modified to express CARs and HLA-G, creating functional copies that don't require the same level of specialized processing infrastructure while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent modifies the HLA expression parameters of allogeneic T cells by deleting endogenous HLA genes and introducing HLA-G expression. This parameter change reduces immune recognition barriers and allows the use of standard processing facilities while maintaining cell persistence and reducing rejection.
2Ease of manufacture
If allogeneic T cells are used in adoptive therapy, then processing complexity is reduced and storage is enabled, but immune reactions occur leading to low persistence and graft-versus-host effects
Solution Approach 1:
The patent extracts and removes endogenous HLA genes from the allogeneic donor T cells through gene deletion. This extraction eliminates the primary target for immune recognition and rejection, allowing the cells to be processed and stored more easily while significantly reducing immune reactions and graft-versus-host effects.
Solution Approach 2:
The patent introduces HLA-G as an intermediary molecule that mediates immune evasion. HLA-G acts as a protective intermediary that reduces T cell and NK cell-mediated rejection while allowing the allogeneic cells to persist in the recipient, thereby enabling easier processing and storage without the usual immune reaction penalties.
3Adaptability or versatility
If T cells express endogenous TCRs, then natural immune function is maintained, but competition with CAR signaling occurs and off-target effects may occur
Solution Approach 1:
The patent extracts and eliminates endogenous TCR expression from the T cells through gene deletion of TCR components. This extraction removes the source of competitive signaling and off-target recognition, ensuring that CAR signaling remains the primary and most reliable activation pathway while maintaining adaptability through CAR design flexibility.
Solution Approach 2:
Instead of trying to enhance natural TCR function to improve adaptability, the patent inverts the approach by eliminating TCR expression entirely and relying solely on CAR-mediated activation. This inversion achieves greater signaling specificity and reliability while maintaining versatility through the programmable nature of CAR antigen specificity.
Data Source
AI summary
The technology described herein relates to modified T cells and their use in immunotherapeutic methods. In various examples, the T cells are modified so as to decrease or eliminate OD3ζ, TRAC, and/or TRBC expression.