Engineered Allogeneic Cells With Immune-Evasion Gene Modulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Allogeneic cell therapies face challenges such as immune rejection and poor cell persistence, limiting their effectiveness in clinical applications.
Innovation Solution
Engineered cells with down-regulated endogenous genes (Fas, TNFR1, DR3, DR4, DR5, TGFBR1, TGFBR2) and expressed exogenous immunosuppressive molecules (e.g., PD1, NKG2A, FasL, CTLA4) to enhance persistence and reduce immune rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic cell therapies are used to improve patient accessibility and reduce preparation time, then productivity and ease of operation are improved, but the risk of immune rejection and poor cell persistence increase, worsening reliability
Solution Approach 1:
The patent applies parameter changes by modifying the genetic expression parameters of allogeneic cells. Specifically, it down-regulates endogenous genes encoding death receptors (Fas, TNFR1, DR3, DR4, DR5, TGFBR1, TGFBR2) and up-regulates exogenous immunosuppressive molecules (PD1, NKG2A, FasL, CTLA4). This genetic parameter modification transforms the cells' immunological properties, enabling them to resist immune rejection while maintaining allogeneic characteristics, thus resolving the contradiction between improved productivity and worsened reliability
Solution Approach 2:
The patent converts the harmful effect of allogeneic immune rejection into a beneficial outcome by engineering the cells to express immunosuppressive molecules. The very mechanism that normally causes rejection (allogeneic differentiation) is transformed into an advantage, as the engineered cells now actively suppress immune responses through expressed molecules like PD1 and CTLA4, turning the harm of allogeneic therapy into a benefit of enhanced persistence and reduced rejection
2Duration of action of moving object
If endogenous genes (Fas, TNFR1, DR3, DR4, DR5, TGFBR1, TGFBR2) are down-regulated to enhance cell persistence, then duration of action is improved, but the complexity of genetic engineering increases, worsening device complexity
Solution Approach 1:
The patent applies segmentation by dividing the genetic engineering task into distinct modular components. It targets specific endogenous genes (Fas, TNFR1, DR3, DR4, DR5, TGFBR1, TGFBR2) for down-regulation and introduces specific exogenous immunosuppressive molecules (PD1, NKG2A, FasL, CTLA4) separately. This segmented approach allows systematic modification of cell properties through targeted gene editing and independent expression cassette integration, making the complex genetic engineering process more manageable and controllable while achieving enhanced cell persistence
3Reliability
If immunosuppressive molecules are expressed to reduce immune rejection, then reliability is improved, but the complexity of cell engineering increases, worsening device complexity
Solution Approach 1:
The patent applies universality by designing immunosuppressive molecule expression cassettes that can be integrated into various allogeneic cell types (T cells, NK cells, CAR-T cells). The same molecular approach (expressing PD1, NKG2A, FasL, or CTLA4) serves multiple functions: suppressing immune rejection, enhancing cell persistence, and maintaining therapeutic activity across different cell platforms. This universal strategy reduces the need for cell-type-specific engineering complexities while achieving reliable immune evasion
Data Source
Figure 1~2B
Figure 3A~4
Figure 5A~6A
AI summary
The present disclosure relates to an engineered cell that expresses an exogenous immunosuppressive molecule and expression of at least one endogenous gene thereof selected from the group consisting of: Fas, TNFR1, DR3, DR4, DR5, TGFBR1 and TGFBR2 is down-regulated. The present disclosure further relates to the engineered cell and a composition comprising the cell.