De-differentiating T Cells for ALS Therapy
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Solution Overview
Problem
Current adoptive T cell therapy for cancer and neurodegenerative diseases faces challenges due to the advanced differentiation state of adult human T cells, which limits their proliferative potential and requires inefficient de-differentiation processes.
Innovation Solution
The method involves de-differentiating T cells using a combination of pharmacologic interventions, such as rapamycin and Vitamin D, and cytokines like IL-2, IL-4, and TGF-β, to convert them into a less differentiated state, followed by differentiation into regulatory T (TREG) or TREG/Th2 cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adult human T cells are used for adoptive therapy, then the therapy can be implemented with available cells, but the advanced differentiation state limits proliferative potential and therapeutic efficacy
Solution Approach 1:
The patent applies preliminary action by de-differentiating T cells before adoptive transfer to restore their proliferative capacity. The method involves treating T cells with specific transcription factors or pharmacologic agents to reverse their differentiation state, thereby preparing them in advance to overcome the limitation of low proliferative potential while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs parameter changes by modifying the differentiation state of T cells through pharmacologic intervention or transcription factor expression. This changes the cellular parameters from an advanced differentiated state to a less differentiated state, thereby improving both proliferative potential and therapeutic efficacy simultaneously
2Productivity
If T cells are de-differentiated using gene transfer methods, then proliferative potential can be restored, but the process is laborious and associated with complications such as teratoma generation
Solution Approach 1:
The patent substitutes mechanical/gene transfer methods with pharmacologic intervention. Instead of using viral or non-viral gene delivery systems to de-differentiate T cells, the invention employs small molecule drugs or pharmacologic agents that achieve the same de-differentiation effect through biochemical pathways, thereby eliminating the complexity and safety issues associated with gene transfer
Solution Approach 2:
The patent uses transient pharmacologic agents instead of permanent genetic modifications. The de-differentiation is achieved through temporary exposure to pharmacologic compounds that do not require integration into the genome, avoiding long-term complications while achieving the desired proliferative potential
3Device complexity
If T cells are de-differentiated using pharmacologic interventions, then the process can be simplified, but the degree of de-differentiation may be insufficient to fully restore proliferative potential
Solution Approach 1:
The patent uses composite pharmacologic approaches by combining multiple agents or using multi-component treatment regimens. This composite strategy enhances the de-differentiation effect beyond what single agents can achieve, fully restoring proliferative potential while maintaining pharmacologic (non-genetic) intervention simplicity
Solution Approach 2:
The patent employs periodic or sequential pharmacologic treatment to achieve cumulative de-differentiation effects. By applying pharmacologic agents in structured cycles or sequences, the method progressively restores proliferative potential while maintaining process simplicity and avoiding genetic modification complexities
Data Source
AI summary
The present disclosure provides methods for treating ALS using pentostatin and cyclophosphamide treatment followed by TREG and/or TREG/Th2 hybrid cells from de-differentiated T cells. The present disclosure further provides methods for producing TREG and TREG/Th2 hybrid cells from de-differentiated T cells, said TREG and TREG/Th2 hybrid cells, populations thereof and compositions thereof. Methods for producing de-differentiated T cells, said de-differentiated T cells, populations thereof and compositions thereof are also provided.