Direct Transdifferentiation of Fibroblasts to Immune Effector Cells
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Solution Overview
Problem
Current methods for generating immune effector CAR T-cells are limited by the need for individual patient production, scalability issues, and complexity, particularly with the use of induced progenitor cells which require skilled personnel and are time-consuming and laborious.
Innovation Solution
The method involves direct transdifferentiation of somatic cells into immune effector cells by inducing expression of specific transcription factors such as Tbet, Tcf7, and Ets1, bypassing the need for pluripotent stem cells and simplifying the process, allowing for scalable and cost-effective production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If induced progenitor cells (iPS) are used to generate immune effector cells, then large numbers of cells can be produced, but the process becomes highly complex and requires highly skilled personnel
Solution Approach 1:
The invention extracts and eliminates the intermediate iPS stage from the cell generation process. By directly transdifferentiating somatic cells into immune effector cells using specific transcription factors (TBET, ETS1, TCF7), the complex multi-step differentiation process is replaced with a streamlined direct conversion approach, maintaining scalability while reducing procedural complexity
Solution Approach 2:
The invention segments the complex differentiation process into a simplified direct transdifferentiation pathway. Instead of the continuous complex differentiation required in iPS methods, the process is segmented into direct conversion using three key transcription factors, making the procedure more manageable and less skill-intensive while still achieving large-scale cell production
2Reliability
If individual patient production is used for CAR T-cells, then autologous cells are obtained, but scalability and economies of scale cannot be achieved
Solution Approach 1:
The invention creates a universal cell production platform that can generate immune effector cells from any patient's somatic cells using the same transcription factor combination (TBET, ETS1, TCF7). This universal approach enables both autologous production (maintaining reliability) and scalable manufacturing (improving productivity) by applying the same methodology across multiple patients simultaneously
3Manufacturing precision
If somatic cells are de-differentiated to iPS and then differentiated to immune effector cells, then effector cells of correct differentiation state can be made, but the process is time consuming and laborious
Solution Approach 1:
The invention performs preliminary action by directly establishing the immune effector cell differentiation program in somatic cells through transcription factor expression, bypassing the time-consuming iPS generation and subsequent differentiation steps. This preliminary direct programming achieves the correct differentiation state while significantly reducing the overall process time and labor requirements
Data Source
AI summary
The invention relates to a method comprising (a) providing a vertebrate somatic cell, (b) inducing expression in said cell of at least three transcription factors, wherein said transcription factors are: i. Tbet (Tbx21), ii. Tcf7, and iii. Ets1; (c) incubating said cell to allow transdifferentiation. Suitably said cell is transdifferentiated to an immune effector cell. The invention also relates to cells, nucleic acids, pharmaceutical compositions, and methods of treatment.