Subset-optimized CAR T Cells Enhancing Persistence and Anti-tumor Activity
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Solution Overview
Problem
Current CAR T cell therapies for cancer treatment face limitations due to poor persistence and anti-tumor activity of infused CAR T cells, necessitating methods to enhance their persistence and efficacy.
Innovation Solution
Engineering CD4+ and CD8+ T cells to express CARs with specific combinations of intracellular signaling domains, differing from each other, to modulate persistence and anti-tumor activity, and administering these cells to patients to treat cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If CAR T cells are engineered with conventional intracellular signaling domains, then anti-tumor activity is achieved, but persistence of the infused T cells is poor
Solution Approach 1:
The patent applies parameter changes by modifying the intracellular signaling domain composition of the CAR molecule. Specifically, it uses combinations of costimulatory domains (such as CD28, 4-1BB, ICOS) with different signaling properties to alter the functional characteristics of CAR T cells. This enables simultaneous improvement of persistence (through costimulatory signals that promote survival) and anti-tumor activity (through appropriate activation signals), resolving the contradiction between duration and reliability.
2Duration of action of moving object
If CAR T cells are engineered to enhance persistence, then duration of action is improved, but the complexity of CAR design increases
Solution Approach 1:
The patent applies segmentation by dividing the intracellular signaling domain into separate functional modules: an antigen recognition domain, a transmembrane domain, and distinct costimulatory domains (first and second costimulatory signals). This modular architecture allows for systematic optimization of persistence without requiring complete redesign of the entire CAR structure, thereby managing complexity while achieving enhanced duration of action.
Solution Approach 2:
The patent employs universal signaling domains that can be combined in different configurations to achieve multiple functions. The same costimulatory domains (CD28, 4-1BB, ICOS) serve both to enhance persistence and to maintain anti-tumor activity, allowing a single CAR design to fulfill multiple objectives without proportionally increasing complexity.
Data Source
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AI summary
This disclosure provides, for instance subset-optimized CART cells and related methods. For instance, the disclosure describes methods and compositions of CD4+ and CD8+ T cells that express CARs containing specific combinations of intracellular signaling domains can be used to increase persistence and anti-tumor activity of the infused CAR-expressing T cells for treating a subject having a disease, e.g., a cancer.