CAR-NK Signaling Design for Solid Tumor Killing
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for natural killer (NK) cells, such as those derived from T cells, face limitations in effectively targeting solid tumors due to impaired NKG2D function and inhibitory receptor signaling, leading to reduced efficacy and safety concerns like cytokine release syndrome and graft-versus-host disease.
Innovation Solution
Design of novel CARs incorporating DAP10 or DAP12 intracellular domains, along with SLAMF receptors and signal boosters like SAP or EAT2, to enhance NK cell activation and overcome inhibitory signaling, enabling robust antigen-specific killing of tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell derived CARs are used in NK cells, then CAR-NK can be produced with off-the-shelf capability and lower safety risks, but anti-tumor activity against solid tumors is reduced due to impaired NKG2D function and inhibitory receptor signaling
Solution Approach 1:
The patent changes the intracellular signaling domain parameters of the CAR by incorporating DAP10 or DAP12 instead of traditional CD3ζ, and adds signal booster domains (SAP, EAT2, or both) to enhance signaling strength. This parameter modification enables the CAR-NK to overcome inhibitory receptor signaling while maintaining the safety profile of NK cell-derived products.
Solution Approach 2:
The patent creates a composite intracellular signaling domain by combining multiple functional elements: the CAR backbone with DAP10/DAP12 intracellular domains, plus signal booster domains (SAP and/or EAT2). This composite structure integrates the advantages of different signaling components to achieve both strong anti-tumor activity and maintained safety.
2Productivity
If NK specific CARs are used, then anti-tumor activity is enhanced, but manufacturing complexity increases compared to T cell derived CARs
Solution Approach 1:
The patent segments the CAR into distinct functional modules: extracellular antigen binding domain, transmembrane domain, and intracellular signaling domain with signal boosters. This modular segmentation allows for systematic design and manufacturing while achieving enhanced anti-tumor activity through the coordinated function of each module.
Solution Approach 2:
The patent creates a universal CAR platform that can be applied to different NK cell sources (allogeneic, autologous, induced pluripotent stem cell-derived) while maintaining enhanced anti-tumor activity. The standardized modular design enables multi-functionality across different cell types and applications.
Data Source
AI summary
The present application relates to chimeric antigen receptors (CARs), engineered immune cells (e.g., NK cells, NKT cells, and T cells), and methods of use thereof. The CARs provided herein can enhance the killing activities of the engineered NK cells.