T Cell Progenitor Maturation-Dependent Transgene Expression
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Solution Overview
Problem
Current cell therapy strategies for treating diseases like cancer face challenges such as graft versus host disease and limited therapeutic activity due to the rapid differentiation of mature T cells, necessitating improved methods for generating modified T-cell progenitors that can navigate thymic selection steps without depletion.
Innovation Solution
The use of T-cell progenitors with an expression cassette containing an exogenous promoter induced by the Notch pathway, specifically the IL7RA or BCL11B promoter, allows for controlled, maturation-dependent expression of a transgene of interest, thereby avoiding expression during critical thymic selection stages and preventing cell depletion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If transgene expression is activated in T-cell progenitors during thymic selection, then therapeutic activity is improved, but cell depletion occurs during negative selection
Solution Approach 1:
The promoter is designed to be dynamically regulated by the Notch pathway, transitioning from an active state during early thymic development to a repressed state during negative selection. This dynamic regulation allows the transgene expression to automatically adapt to different developmental stages, ensuring cell survival during critical selection periods while maintaining therapeutic function in mature T cells
Solution Approach 2:
The invention changes the regulatory parameter of promoter activity through Notch pathway signaling. When Notch is activated during thymic selection, it modulates the promoter's transcriptional activity, thereby controlling transgene expression levels. This parameter change enables the system to respond to physiological cues and adjust expression accordingly, preventing cell depletion while preserving therapeutic potential
2Speed
If mature T cells are used for therapy, then immediate therapeutic effect is achieved, but rapid differentiation limits persistence
Solution Approach 1:
The invention performs preliminary action by genetically modifying T-cell progenitors ex vivo before their natural maturation and expansion in the host thymus. This allows the therapeutic transgene to be integrated into the germline of the developing T cells, ensuring that all subsequent mature T cells inherit the modification. This preliminary genetic engineering enables long-term persistence while maintaining the natural maturation timeline for rapid therapeutic response
3Quantity of substance
If allogeneic mature T cells are used, then cell availability is improved, but graft versus host disease occurs
Solution Approach 1:
The invention extracts the problematic TCR repertoire from the therapeutic cells by using T-cell progenitors instead of mature T cells. By targeting the progenitor stage, the system allows the host thymus to naturally select and shape the TCR repertoire, effectively removing autoreactive and host-reactive T cells through physiological negative selection. This extraction of the dangerous repertoire while retaining therapeutic potential prevents GvHD
Solution Approach 2:
The host thymus acts as an intermediary that naturally processes and selects the TCR repertoire of the allogeneic progenitors. Through the host's own selection mechanisms, the system achieves automatic purification of the cell population, removing cells that would cause GvHD while preserving those with appropriate host tolerance. This intermediary selection process eliminates the need for manual repertoire manipulation
Data Source
AI summary
The invention relates to a progenitor T cell comprising an expression cassette that enables controlled expression of a trans gene of interest based on the stage of maturation of said progenitor T cell. The invention also relates to a cell population enriched in progenitor T cells of this kind, to a process for preparing progenitor T cells, and to the use of said cells in a treatment method.