Rejuvenated T Cells via Transient Reprogramming Factors
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Solution Overview
Problem
Tumor Infiltrating Lymphocytes (TILs) used in cancer therapies often exhibit cellular markers of extensive differentiation and aging, leading to loss of functionality and poor clinical efficacy.
Innovation Solution
A method involving the transient expression of reprogramming factors such as KLF4, OCT3/4, SOX2, and C-MYC in T cells, without transforming them into induced Pluripotent Stem (iPS) cells, followed by contact with T cell activating agents to produce rejuvenated T cells with enhanced anti-tumor function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TILs are used in cancer therapy, then anti-tumor function is achieved, but cellular differentiation and aging markers increase leading to loss of functionality
Solution Approach 1:
The patent applies parameter changes by transiently expressing reprogramming factors (KLF4, OCT3/4, SOX2, C-MYC) in TILs to modify their epigenetic state and cellular phenotype. This temporary genetic intervention reverses differentiation and aging markers while maintaining anti-tumor functionality, directly addressing the contradiction between functional efficacy and cellular stability
Solution Approach 2:
The patent employs partial reprogramming rather than complete iPS cell differentiation. By using transient expression of reprogramming factors and limiting the reprogramming process to specific temporal windows, the method achieves sufficient reversal of aging markers without over-stepping into full pluripotency, thus maintaining T cell functionality while improving cellular composition stability
2Stability of the object's composition
If complete reprogramming to iPS cells is performed, then biological clock is reset, but abnormal biology and immature phenotype occur
Solution Approach 1:
The patent deliberately applies partial reprogramming action by using transient expression of reprogramming factors for limited durations. This partial action is sufficient to reset the biological clock and reverse aging markers but falls short of complete iPS cell differentiation, avoiding the emergence of abnormal biology and immature phenotypes while maintaining reliable T cell functionality
Solution Approach 2:
The patent performs preliminary reprogramming action by introducing reprogramming factors before the T cells reach a fully differentiated and aged state. This timing intervention allows epigenetic resetting to occur in advance, preventing the accumulation of irreversible aging markers while avoiding the need for complete reprogramming to iPS cells
3Manufacturing precision
If 3D thymic organoid cultures are used for differentiation, then developmentally homogeneous T cells are produced, but time and resource intensity increase
Solution Approach 1:
The patent changes the temporal parameter of reprogramming by using transient, short-term expression of reprogramming factors rather than prolonged culture periods. This time-efficient approach achieves sufficient epigenetic resetting and phenotypic improvement without requiring the extended time necessary for 3D thymic organoid differentiation, thus reducing time loss while maintaining acceptable manufacturing precision
Data Source
AI summary
The present disclosure relates generally to methods of producing rejuvenated T cells, comprising, contacting T cells with at least one reprogramming factor and reactivating the contacted cells; and compositions and methods of using same. The present disclosure also describes cell populations prepared according to methods described herein. The disclosure also provides for methods of treating patients using cell populations prepared by the methods described herein.