TCR-Reduced Modified T Cells for Universal Cell Therapy
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Solution Overview
Problem
Current adoptive T cell therapy faces challenges with autologous cell use, requiring specialized personnel and facilities, and allogeneic cell therapy is hindered by immune reactions and persistence issues.
Innovation Solution
Modified T lymphocytes with reduced or eliminated T Cell Receptor (TCR) expression, such as through gene mutations or deletions, and the introduction of heterologous proteins like viral proteins to evade immune attack, combined with chimeric antigen receptors (CARs) for targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic T cells are used for adoptive cell therapy, then cell availability and scalability are improved, but immune rejection and persistence are worsened
Solution Approach 1:
The patent extracts and removes the T cell receptor (TCR) from allogeneic T cells through genetic modification (deletion of TRAC and/or TRBC genes). This extraction eliminates the source of alloreactivity while preserving the cytotoxic function of the T cells, allowing them to persist in the host without being rejected by the host immune system.
Solution Approach 2:
The patent introduces chimeric antigen receptors (CARs) as intermediary structures that mediate antigen recognition and T cell activation without requiring endogenous TCR-HLA interactions. The CAR provides a new signaling pathway that bypasses the host immune system's recognition of allogeneic HLA molecules, enabling persistence.
2Reliability
If T cell receptor (TCR) expression is maintained in allogeneic T cells, then native T cell function is preserved, but host-versus-graft and graft-versus-host reactions occur
Solution Approach 1:
The patent removes the TCR complex from allogeneic T cells by deleting essential components (TRAC and/or TRBC genes), thereby eliminating the ability to form functional TCR-HLA complexes that would trigger alloreactive responses between donor and host immune systems.
Solution Approach 2:
The patent fundamentally changes the antigen recognition parameter by replacing TCR-based recognition with CAR-based recognition. This parameter change allows the T cells to function cytotoxically against target antigens without relying on TCR expression, thus avoiding alloreactivity.
3Object-affected harmful factors
If autologous T cells are used for therapy, then immune rejection is minimized, but specialized facilities and processing time are required
Solution Approach 1:
The patent creates universal allogeneic T cell products that can be manufactured once and used for multiple patients. The genetically modified T cells with deleted TCR genes and engineered CARs function as a universal therapy, eliminating the need for individualized autologous cell processing while maintaining therapeutic efficacy.
Solution Approach 2:
The patent performs genetic modification (TCR deletion and CAR insertion) in advance during manufacturing, creating pre-modified allogeneic T cells that can be stored and administered without requiring complex real-time processing at the patient site. This preliminary action simplifies the clinical workflow.
Data Source
AI summary
The invention provides modified an isolated T lymphocytes having reduced or eliminated expression of the T Cell Receptor, due to reduced or eliminated expression of a CD3ζ, T Cell Receptor Alpha Chain, or T Cell Receptor Beta Chain gene relative to a T lymphocyte without modification, where the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal peptide, and UL18.