NK Cell CAR Constructs for Reduced Cytokine Release
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Solution Overview
Problem
Current CAR-T cell therapies for cancer often result in cytokine release syndrome (CRS) and organ failure due to T cell overactivity, highlighting the need for CAR technology optimized for Natural Killer (NK) cells, which can offer lower CRS and neurotoxicity risks with 'off-the-shelf' manufacturing feasibility.
Innovation Solution
Development of Chimeric Antigen Receptor (CAR) constructs specifically designed for NK cells, comprising extracellular binding domains, transmembrane domains, and intracellular signaling or co-stimulatory domains tailored for NK cell activation, such as using NK cell receptors like 2B4, NTB-A, CRACC, and CD2, and co-stimulatory receptors like 4-1BB and IL2RB, to enhance anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat cancer, then anti-tumor activity is improved, but cytokine release syndrome and organ failure occur due to T cell overactivity
Solution Approach 1:
The patent changes the cell type parameter from T cells to NK cells, and modifies the CAR construct parameters (transmembrane domain, intracellular signaling domains) to be optimized for NK cell biology. This results in reduced cytokine release syndrome while maintaining anti-tumor activity, as NK cells have different activation thresholds and cytokine profiles compared to T cells
Solution Approach 2:
The patent creates a CAR-NK system that copies the successful CAR-T approach but adapts it for NK cells. The CAR construct design is replicated from CAR-T but modified with NK cell-specific components (NK cell-derived transmembrane domains, signaling domains like DAP10, DAP12, FcRγ) to achieve similar anti-tumor efficacy with reduced toxicity
2Ease of manufacture
If CAR constructs designed for T cells are used in NK cells, then manufacturing feasibility is improved, but NK cell activation and anti-tumor activity are insufficient
Solution Approach 1:
The patent modifies the CAR construct parameters to include NK cell-specific transmembrane domains (e.g., from NKp46, NKG2D, CD16) and intracellular signaling domains (e.g., DAP10, DAP12, FcRγ chains) that are optimized for NK cell activation pathways. This enables both off-the-shelf manufacturing and potent NK cell activation with enhanced cytotoxic activity
Data Source
AI summary
The technology described herein is directed to Natural Killer (NK) cell CAR polypeptides comprising intracellular signaling domains, intracellular costimulatory domains, and/or transmembrane domains from NK-associated polypeptides. In various aspects, described herein are polynucleotides, vectors, or cells expressing said NK CAR polypeptides, and pharmaceutical compositions comprising said NK CAR polypeptides, polynucleotides, vectors, or cells. Also described herein are methods of using said NK CAR polypeptides, for example to treat various diseases and disorders, such as cancer or infectious diseases.