ICOS Domain CAR Enhances Th17 Persistence and Anti-Tumor Activity
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Solution Overview
Problem
Current cancer therapies lack effective methods to enhance the anti-tumor activity and persistence of genetically redirected Th17 cells, which are crucial for tumor immunity and treatment outcomes.
Innovation Solution
Development of a chimeric antigen receptor (CAR) comprising an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain, specifically designed for T cells to increase IL-17 production and anti-tumor activity, while reducing IL-2 production and promoting T cell persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR designs are used to redirect T cells, then antigen recognition is achieved, but anti-tumor activity and cell persistence are insufficient
Solution Approach 1:
The patent combines multiple functional domains into a single CAR structure: the antigen-binding domain (anti-CD19 scFv), transmembrane domain (CD8α hinge and transmembrane region), and intracellular signaling domain (ICOS). This merging of components into one integrated receptor enables simultaneous antigen recognition, membrane anchoring, and costimulatory signaling, thereby enhancing anti-tumor activity and T cell persistence without requiring multiple separate molecular components
Solution Approach 2:
The CAR construct functions as a composite molecular structure integrating elements from different sources: the variable region from an anti-CD19 antibody, the transmembrane and hinge regions from CD8α, and the intracellular domain from ICOS. This composite design combines the antigen-specific binding capability of antibodies with the costimulatory signaling functions of T cell receptors, creating a hybrid receptor that achieves superior anti-tumor efficacy
2Quantity of substance
If Th17 cells are used for tumor immunity, then IL-17 production is enhanced, but cell persistence and anti-tumor activity remain insufficient
Solution Approach 1:
The patent modifies the intracellular signaling parameters of Th17 cells by introducing the ICOS domain into the CAR structure. This parameter change in the signaling pathway alters the functional output of the cells, leading to enhanced IL-17 production and improved persistence. The ICOS domain provides specific costimulatory signals that change the activation state and survival characteristics of the redirected Th17 cells
3Duration of action of stationary object
If ICOS domain is added to CAR structure, then T cell persistence and anti-tumor activity are enhanced, but receptor complexity increases
Solution Approach 1:
The ICOS domain is incorporated into the CAR structure during the initial gene transduction step, before T cell activation and expansion. This preliminary incorporation ensures that the costimulatory signaling capability is built into the receptor from the outset, allowing for enhanced persistence and anti-tumor activity to manifest during subsequent cell activation and tumor challenge without requiring additional molecular modifications or complex multi-step processes
Data Source
AI summary
The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a genetically modified Th17 cell to express a CAR having an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.