ITAM-Mutated CARs with Inducible IL-18 Receptors for T Cell Persistence
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Solution Overview
Problem
Challenges in CAR T cell therapy include rapid exhaustion and inefficacy against low antigen-expressing cancer cells, particularly in solid tumors, leading to early cancer recurrence.
Innovation Solution
Immune cells expressing a chimeric antigen receptor (CAR) with ITAM mutations and an inducible IL-18 receptor alpha, which enhances persistence and killing ability against low antigen-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to target low antigen-expressing cancer cells, then the ability to kill cancer cells is improved, but rapid exhaustion occurs leading to early cancer recurrence
Solution Approach 1:
The patent implements dynamic regulation of the IL-18 receptor through an inducible expression system that responds to antigen stimulation. When the CAR binds to antigen, signaling pathways activate the inducible promoter, increasing IL-18 receptor expression on the cell surface. This dynamic adjustment allows the T cell to adapt its cytokine reception capacity based on the antigen environment, preventing exhaustion while maintaining persistence.
Solution Approach 2:
The patent changes the expression level parameter of the IL-18 receptor by introducing an inducible expression system. The receptor expression level is not fixed but can be modulated in response to antigen stimulation, allowing the system to optimize its functional parameters adaptively. This parameter change enables the T cell to maintain high IL-18 receptor expression when needed while avoiding constitutive overexpression issues.
2Duration of action of moving object
If the IL-18 receptor is constitutively expressed to enhance persistence, then CAR T cell persistence is improved, but the system becomes less adaptable to varying antigen environments
Solution Approach 1:
The inducible expression system transforms the static, constitutive expression of the IL-18 receptor into a dynamic, regulated system. The receptor expression level changes in response to antigen stimulation through signaling pathways that activate the inducible promoter. This dynamic behavior provides adaptability to varying antigen environments while maintaining persistence benefits.
3Duration of action of moving object
If ITAM mutations are introduced in the CAR to reduce exhaustion, then CAR T cell persistence is improved, but the signaling strength may be reduced
Solution Approach 1:
The patent combines ITAM-mutated CAR with an inducible IL-18 receptor expression system to create a synergistic effect. The ITAM mutations provide baseline persistence benefits by reducing exhaustion, while the inducible IL-18 receptor adds an adaptive layer that enhances persistence further when activated. This merging of two different mechanisms (ITAM mutation and inducible cytokine reception) achieves enhanced persistence without relying solely on one approach that might compromise signaling strength.
Data Source
AI summary
Disclosed herein are compositions comprising an interleukin-18 (IL-18) receptor amino acid sequence that comprises an IL-18 receptor extracellular domain or a polynucleotide that encodes an IL-18 receptor amino acid sequence that comprises an IL-18 receptor extracellular domain and a chimeric antigen receptor (CAR) amino acid sequence or a polynucleotide that encodes a CAR amino acid sequence. In some embodiments the CAR targets MUC1 or MUC1*.