Immune Cells Modulating T-bet Eomes c-Myb for Anti-Tumor Activity
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Solution Overview
Problem
Aged immune effector cells, such as those from donors over 24 years old, exhibit reduced anti-tumor activity due to terminal differentiation and a lower CD4/CD8 ratio, leading to decreased central memory cells and increased terminally differentiated cells, which hampers their effectiveness in cancer treatment.
Innovation Solution
Genetic modification of immune effector cells to regulate the expression of transcription factors like T-bet, Eomes, and c-Myb to increase the CD4/CD8 ratio, reversing terminal differentiation and enhancing anti-tumor activity by skewing the phenotype towards young, central memory-like cells, thereby improving their anti-tumor efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If aged immune effector cells are used for cancer treatment, then the treatment can be provided to elderly patients, but the anti-tumor activity is reduced due to terminal differentiation and lower CD4/CD8 ratio
Solution Approach 1:
The patent changes the biological parameters of aged T cells by genetically modifying transcription factor expression (T-bet, Eomes, c-Myb) to reverse terminal differentiation, increase central memory cell formation, and improve the CD4/CD8 ratio, thereby restoring anti-tumor activity while maintaining availability for elderly patients
Solution Approach 2:
The patent applies preliminary genetic modification to aged T cells before adoptive transfer to reverse terminal differentiation and establish a more youthful phenotype with enhanced memory differentiation and anti-tumor capacity, preparing the cells in advance to overcome age-related functional decline
2Reliability
If transcription factor expression is modified to increase CD4/CD8 ratio, then central memory cells are increased and terminal differentiation is reversed, but genetic modification complexity increases
Solution Approach 1:
The patent segments the genetic modification approach by targeting specific transcription factors (T-bet, Eomes, c-Myb) individually or in combination, allowing systematic optimization of central memory cell formation without requiring comprehensive genomic modification
Solution Approach 2:
The patent uses transcription factors as intermediary molecules that mediate the conversion of aged T cells to a more youthful phenotype, acting as key regulators that coordinate multiple downstream effects including memory differentiation and cytokine production without requiring direct manipulation of all cellular components
Data Source
AI summary
Disclosed herein are recombinant immune effector cells genetically modified to regulate expression of one or more transcription factors selected from T-bet, Eomes, and c-Myb. In some embodiments, the cells are modified to express recombinant T-bet, Eomes, c-Myb, or any combination thereof. In some embodiments, the cells are modified to express recombinant dominant negative forms of T-bet, Eomes, c-Myb, or any combination thereof to inhibit the activity of endogenous transcription factors. In some embodiments combinations of these approaches are used to increase expression of one or more of T-bet, Eomes, c-Myb while inhibiting the activity of one or more of T-bet, Eomes, and c-Myb.