Chimeric Tim4 Receptors for T Cell Exhaustion
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for cancer, such as chemotherapy and CAR-T cell therapy, can lead to T cell exhaustion, reducing their effectiveness in targeting and eliminating tumor cells.
Innovation Solution
The development of chimeric Tim4 receptors, which are engineered to confer engulfment and cytotoxic activity to T cells, allowing them to recognize and eliminate tumor cells by binding to phosphatidylserine, a marker exposed on stressed or apoptotic cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cell therapy is used to target tumor cells, then initial anti-tumor activity is achieved, but T cell exhaustion develops leading to reduced effectiveness over time
Solution Approach 1:
The patent combines multiple signaling domains (CD3ζ for antigen recognition, CD28 for costimulation, and TLR for innate immune signaling) into a single chimeric receptor construct. This merging of signaling pathways enables T cells to receive integrated signals that simultaneously drive activation, proliferation, and resistance to exhaustion, thereby maintaining anti-tumor effectiveness over extended periods
Solution Approach 2:
The chimeric Tim4 receptor functions as a composite signaling molecule integrating extracellular Tim4 binding domain with multiple intracellular signaling domains. This composite structure allows the receptor to mediate both antigen-specific recognition and broad costimulatory signaling, creating a synergistic effect that prevents T cell exhaustion and sustains long-term anti-tumor activity
2Duration of action of stationary object
If prolonged antigen exposure occurs to maintain T cell activation, then tumor cell recognition is sustained, but T cell exhaustion ensues with impaired effector function
Solution Approach 1:
The chimeric receptor design enables continuous useful action by providing sustained costimulatory signaling through the integrated CD28 and TLR domains. This continuous signaling prevents the interruption of T cell activation that would otherwise lead to exhaustion, maintaining effector function over prolonged periods of antigen exposure
Solution Approach 2:
The TLR domain in the chimeric receptor provides feedback signaling that monitors the activation state and adjusts costimulatory signals accordingly. This feedback mechanism prevents overactivation and subsequent exhaustion, allowing sustained effector function without triggering the dysfunctional state associated with prolonged antigen exposure
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These chimeric Tim4 receptors enhance the antigen presentation capacity of T cells, improve their cytotoxic activity, and reduce T cell exhaustion, leading to increased efficacy in targeting and eliminating tumor cells.
Implementation Method 1
chimeric Tim4 receptors, which are engineered to confer engulfment and cytotoxic activity to T cells, allowing them to recognize and eliminate tumor cells by binding to phosphatidylserine, a marker exposed on stressed or apoptotic cells
Implementation Method 2
chimeric Tim4 receptors, which are engineered to confer engulfment and cytotoxic activity to T cells
Implementation Method 3
chimeric Tim4 receptors, which are engineered to confer engulfment and cytotoxic activity to T cells
Data Source
AI summary
The present disclosure relates to chimeric Tim receptors, host cells modified to include chimeric Tim receptor molecules, and methods of making and using such receptor molecules and modified cells.