Pre-Activated NK Cell Expansion Using CD137L aAPCs
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Solution Overview
Problem
Existing methods for activating and expanding natural killer (NK) cells for therapeutic use are limited by the need for complex and costly procedures like leukapheresis to obtain sufficient numbers, and there is a lack of effective strategies for producing highly functional pre-activated NK cells.
Innovation Solution
A method involving pre-activation of NK cells with IL-12, IL-15, and IL-18 followed by expansion using artificial antigen presenting cells (aAPCs) expressing CD137 ligand, such as engineered K562 cells, to produce expanded NK cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If NK cells are directly isolated from peripheral blood without ex vivo expansion, then the procedure is simpler, but the number of NK cells obtained is insufficient for therapeutic applications
Solution Approach 1:
The patent applies preliminary action by performing ex vivo expansion of NK cells before therapeutic administration. NK cells are isolated from peripheral blood, pre-activated with cytokines (IL-12, IL-15, IL-18), and then expanded in culture using artificial antigen-presenting cells expressing CD137 ligand. This preliminary expansion step generates sufficient numbers of functional NK cells for therapeutic use, resolving the contradiction between obtaining adequate cell numbers and maintaining procedural simplicity.
2Quantity of substance
If leukapheresis is used to obtain sufficient NK cells, then adequate numbers can be obtained, but the procedure is complicated and costly
Solution Approach 1:
The patent employs self-service by enabling NK cells to expand and proliferate autonomously in vitro through engagement with artificial antigen-presenting cells. The aAPCs expressing CD137 ligand provide continuous stimulation that triggers NK cell self-renewal and expansion, eliminating the need for complex leukapheresis procedures. This self-expansion mechanism generates sufficient cell numbers while maintaining procedural ease and reducing costs.
3Reliability
If NK cells are pre-activated with IL-18, IL-15, and IL-12, then functional competency is enhanced, but the production scale is limited without effective expansion strategy
Solution Approach 1:
The patent introduces an intermediary system using artificial antigen-presenting cells (aAPCs) as mediators between pre-activated NK cells and therapeutic production. The aAPCs express CD137 ligand and membrane-bound cytokines (IL-21 or IL-15), providing continuous stimulatory signals that drive large-scale expansion of pre-activated NK cells. This intermediary mechanism resolves the contradiction by enabling both enhanced functional competency (through pre-activation) and large-scale production (through aAPC-mediated expansion).
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 method results in enhanced anti-tumor functionality and antibody-dependent cellular cytotoxicity of NK cells, with improved cytotoxicity and cytokine production against leukemia and lymphoma cell lines, and supports large-scale 'off-the-shelf' production for therapeutic applications.
Implementation Method 1
expanding the pre-activated NK cells in an expansion culture comprising artificial antigen presenting cells (aAPCs) expressing CD137 ligand
Implementation Method 2
pre-activating the population of NK cells in a pre-activation culture comprising an effective concentration of IL-12, IL-15, and IL-18
Data Source
AI summary
Provided herein are methods for pre-activating and expanding an isolated population of NK cells. Further provided herein are methods for the treatment of cancer by administering the pre-activated and expanded NK cells.