Modified NK Cells for Immunotherapy via CRISPR Knockout
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Solution Overview
Problem
Current immunotherapy approaches using NK cells in immunooncology have seen limited success due to suboptimal NK cell responses, primarily because tumors harness inhibitory pathways to suppress cytotoxic activity, proliferation, and survival of NK cells, leading to inadequate therapeutic outcomes in treating solid tumors.
Innovation Solution
Development of modified NK cells derived from induced pluripotent stem cells (iPSCs) with specific genomic edits, such as loss-of-function in inhibitory receptors and expression of enhanced activating receptors, using RNA-guided nuclease technology to engineer cells with improved survival, proliferation, and resistance to exhaustion, enabling enhanced therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally occurring or modified NK cells are used in immunotherapy approaches, then some therapeutic success has been achieved, but the NK cell response remains suboptimal due to tumor suppression mechanisms
Solution Approach 1:
The patent applies parameter changes by modifying the genetic composition of NK cells through CRISPR-Cas9 technology. Specifically, it knocks out inhibitory receptors (NKG2A, PD-1, TIGIT) and enhances activating receptors (DNAM-1, 2B4) to change the functional parameters of NK cells, thereby improving their therapeutic efficacy and response against tumors that normally suppress NK cell activity
Solution Approach 2:
The patent extracts and removes the harmful inhibitory components from NK cells by knocking out the genes encoding inhibitory receptors (NKG2A, PD-1, TIGIT). This extraction of suppressive elements allows the NK cells to function more effectively without being inhibited by tumor-derived ligands, thus improving the suboptimal NK cell response
2Object-affected harmful factors
If tumors harness inhibitory pathways to suppress NK cell activity, then NK cell cytotoxic activity is limited, but this suppression mechanism prevents adequate therapeutic outcomes
Solution Approach 1:
The patent converts the harmful tumor suppression mechanism into a benefit by targeting and eliminating the very inhibitory pathways that tumors exploit. By knocking out NKG2A, PD-1, and TIGIT receptors, the NK cells are rendered resistant to tumor suppression mechanisms, transforming the previously harmful inhibitory interactions into a therapeutic advantage where NK cells can effectively recognize and kill tumor cells despite tumor immune evasion strategies
Solution Approach 2:
The patent applies preliminary anti-action by pre-equipping NK cells with genetic modifications that block inhibitory pathways before the cells encounter tumors. The CRISPR-Cas9 mediated knockout of inhibitory receptors (NKG2A, PD-1, TIGIT) is performed in advance, so that when these NK cells are administered therapeutically, they are already protected against tumor suppression mechanisms rather than being suppressed upon contact with tumor cells
3Reliability
If genomic edits are introduced to enhance NK cell function, then survival and proliferation are improved, but the complexity of cell engineering increases
Solution Approach 1:
The patent applies self-service by utilizing the CRISPR-Cas9 system's ability to automatically target and edit specific genomic loci based on guide RNA sequences. The system self-assembles the editing machinery at the correct genomic locations (NKG2A, PD-1, TIGIT, DNAM-1, 2B4 genes) and performs the knockout or enhancement operations without requiring complex external intervention, thereby improving NK cell survival and proliferation while managing engineering complexity through the system's inherent precision and automation
Data Source
AI summary
The present disclosure is directed to the generation of NK cells (or other lymphocytes) from induced pluripotent cells that have been derived from cells, e.g., developmentally mature T cells, and uses thereof for immunotherapy.