Dual CISH CD38 Knockout NK Cells Enhance Cytotoxicity and Persistence
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Solution Overview
Problem
Current immune cell therapies, such as those using natural killer (NK) cells, face challenges in effectively targeting and killing cancer cells due to limitations in cytotoxicity and persistence, particularly against cancer cells that evade immune responses by downregulating major histocompatibility complex (MHC) class I expression and dampening NK cell activity.
Innovation Solution
Modified NK cells and cell lines with reduced CIS and CD38 function, optionally lacking checkpoint inhibitory receptors and expressing TRAIL ligands, chimeric antigen receptors, and growth-promoting cytokines, are engineered to enhance cytotoxicity and persistence, using CRISPR gene editing for efficient modification and rapid transfection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If CIS expression is knocked out to enhance cytotoxicity, then cytotoxic activity against cancer cells is improved, but cell persistence is decreased
Solution Approach 1:
The patent applies parameter changes by simultaneously modifying two genetic parameters: knocking out CIS (CISH gene) to enhance cytotoxic activity and knocking out CD38 to improve cell persistence. This dual genetic modification resolves the contradiction by changing the biological parameters of the NK cells to achieve both enhanced killing ability and improved survival in vivo.
2Reliability
If multiple genetic modifications are applied to enhance cytotoxicity and persistence, then therapeutic effectiveness is improved, but transfection complexity increases
Solution Approach 1:
The patent merges multiple genetic modification operations into a single transfection process by co-delivering CRISPR/Cas9 components targeting both CISH and CD38 genes simultaneously. This combining approach reduces the number of separate transfection steps required while achieving the desired dual knockout, thereby improving therapeutic effectiveness without proportionally increasing transfection complexity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified NK cells demonstrate increased cytotoxicity, persistence, and metabolic resilience, effectively targeting and killing cancer cells, including those resistant to immune responses, with improved transfection efficiency and reduced vulnerability to microenvironmental changes.
Implementation Method 1
using CRISPR gene editing for efficient modification and rapid transfection
Data Source
AI summary
NK cells and NK cell lines are modified to increase their cytotoxicity. proliferation. metabolic profile and persistence. wherein the cells and compositions thereof have a use in the treatment of cancer. Production of modified NK cells and NK cell lines is via genetic modification to knockout expression of both CISH and CD38 genes