Modified T Cells Evading Immune Rejection via TCR Elimination
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Solution Overview
Problem
Current adoptive T cell therapy faces challenges such as the need for specialized personnel and facilities, complexity in obtaining cells from ill patients, and immune reactions against allogeneic cells, leading to low persistence and graft-versus-host effects.
Innovation Solution
Modified T lymphocytes with reduced or eliminated expression of the T Cell Receptor (TCR) genes, such as CD3ζ, TRAC, and TRBC, are engineered to express heterologous viral proteins that facilitate immune evasion, allowing for the use of allogeneic cells that can persist longer and reduce immune rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic T cells are used in adoptive therapy, then cell availability and standardization are improved, but immune rejection and graft-versus-host effects increase
Solution Approach 1:
The patent extracts and eliminates the endogenous T cell receptor (TCR) and CD3ζ genes from the allogeneic T cells, removing the primary mediators of immune recognition and rejection. This allows the cells to evade host immune surveillance while maintaining their therapeutic function through alternative mechanisms.
Solution Approach 2:
The patent introduces heterologous viral proteins as intermediary molecules that mediate immune evasion. These viral proteins act as decoys or inhibitors that interfere with host immune recognition mechanisms, enabling the allogeneic T cells to persist without triggering strong rejection responses.
2Object-affected harmful factors
If TCR and CD3ζ genes are eliminated, then immune rejection is reduced, but T cell activation and specificity may be compromised
Solution Approach 1:
The patent creates a multi-functional T cell system where the eliminated TCR/CD3ζ pathway is compensated by alternative activation mechanisms. The T cells can be activated through non-TCR pathways such as CD3ε signaling or costimulatory molecules, providing redundant activation routes that maintain reliability while reducing rejection.
Solution Approach 2:
The patent fundamentally changes the activation parameters of the T cells by shifting from TCR-mediated activation to alternative activation pathways. This parameter change allows the cells to function without traditional TCR engagement, reducing immune recognition while maintaining therapeutic efficacy.
3Object-affected harmful factors
If heterologous viral proteins are expressed, then immune evasion is enhanced, but risk of viral reactivation and immune reactions increases
Solution Approach 1:
The patent employs transient expression of heterologous viral proteins that are designed to be short-lived and non-integrating. These proteins are expressed only during the therapeutic window and then degraded, minimizing the risk of persistent viral reactivation while providing sufficient immune evasion during the critical treatment period.
Solution Approach 2:
The patent converts the potentially harmful viral proteins into beneficial immune evasion tools by carefully selecting viral genes that provide protection without causing disease. The viral proteins are used in a controlled manner to shield the T cells, and any potential harm is mitigated through selective gene choice and transient expression strategies.
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 CD3ζ, TRAC, and/or TRBC expression.