Modified T Cells Expressing Dominant Negative DR5 for CAR-T Therapy
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in overcoming tumor immune suppression and metabolic hostile tumor microenvironments, limiting their effectiveness in cancer treatment.
Innovation Solution
Development of modified T cells expressing a dominant negative form of Death receptor 5 (DR5) and a chimeric antigen receptor (CAR) that binds to specific tumor antigens, enhancing T cell response and persistence in the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to target malignancies, then anti-tumor efficacy is improved, but tumor immune suppression and metabolic hostile microenvironment limit effectiveness
Solution Approach 1:
The patent converts the harmful effect of tumor-derived TRAIL (which normally induces apoptosis in T cells) into a beneficial signal by engineering T cells to express a dominant-negative DR5 receptor. This mutated receptor binds TRAIL but prevents apoptosis signaling, transforming the tumor's immune suppression mechanism into a survival advantage for the T cells.
Solution Approach 2:
The T cells are pre-engineered with the dominant-negative DR5 expression before encountering the tumor microenvironment. This preliminary modification prevents the harmful apoptotic effect from taking place, allowing the T cells to survive and persist in the hostile tumor environment without being eliminated by TRAIL-mediated apoptosis.
2Reliability
If T cells are engineered to attack patient's cancer, then T cell response is enhanced, but metabolic hostile tumor microenvironment reduces persistence
Solution Approach 1:
The patent transforms the metabolic stress and TRAIL-mediated apoptosis signals from the tumor microenvironment into survival signals by expressing dominant-negative DR5. This allows T cells to not only respond to tumor antigens but also persist longer in the metabolically hostile environment by blocking the apoptotic pathway that would normally eliminate them.
Solution Approach 2:
The patent changes the apoptotic sensitivity parameter of T cells by introducing the dominant-negative DR5 receptor. This modification alters the T cell's response to TRAIL signaling, changing from apoptosis induction to apoptosis inhibition, thereby extending T cell lifespan and persistence in the tumor microenvironment.
3Reliability
If genome editing is used to disrupt gene expression in T cells, then effector functions are enhanced, but cellular complexity increases
Solution Approach 1:
The patent segments the complex genome editing process into a focused single-gene modification approach. Instead of making multiple genetic changes to enhance various T cell functions, the invention uses a single dominant-negative DR5 transgene to address multiple problems (TRAIL sensitivity, persistence) simultaneously, reducing overall cellular complexity while maintaining enhanced effector functions.
Data Source
AI summary
Embodiments relate to a modified cell comprising a polynucleotide encoding a dominant negative form of Death receptor 5 (DR5). In embodiments, the modified cell further comprises a chimeric antigen receptor (CAR) and/or a modified TCR.