M-CENK Cell Preparation for Stable CD16 Expression and Faster ADCC
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Solution Overview
Problem
Existing methods for producing memory-like cytokine-enhanced natural killer (M-CENK) cells from apheresis products face challenges in achieving stable CD16 expression and efficient tumor killing via antibody-dependent cell-mediated cytotoxicity (ADCC), and there is a need for faster production to treat cancer patients effectively.
Innovation Solution
A method involving the depletion of CD3+ and CD14+ cells from a blood sample to create a CD3− CD14− population, followed by incubation with cytokine compositions of IL-15, IL-18, and IL-12 derivatives to produce CD56+ enriched M-CENK cells with enhanced CD16 expression, which can be administered within 10-12 days.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional apheresis products are used to generate M-CENK cells, then cell expansion can be achieved, but CD16 expression is unstable and insufficient for effective ADCC
Solution Approach 1:
The patent applies preliminary action by depleting CD3+ and CD14+ cells from the apheresis product before cytokine-induced expansion. This pre-processing step creates a purified CD3− CD14− population that serves as an optimized starting material, enabling more stable CD16 expression and enhanced ADCC capability in the subsequent M-CENK cell generation
Solution Approach 2:
The patent employs parameter changes by modifying the cell population composition through selective depletion of specific cell types (CD3+ and CD14+ cells). This changes the fundamental parameters of the starting material, resulting in a purified population with enhanced ability to express CD16 stably during cytokine-induced expansion
2Reliability
If extended cultivation time is used to improve CD16 expression, then ADCC capability increases, but production time for patient treatment increases
Solution Approach 1:
By performing CD3+ and CD14+ cell depletion as a preliminary step, the patent creates an optimized starting population that requires less cultivation time to achieve stable CD16 expression. This pre-enrichment of the correct cell population accelerates the overall production timeline while maintaining high CD16 expression levels
Solution Approach 2:
The patent extracts and removes unwanted cell types (CD3+ T cells and CD14+ monocytes) from the apheresis product before expansion. This extraction step eliminates cells that would interfere with CD16 expression stability, allowing the remaining CD3− CD14− population to expand more efficiently with higher CD16 expression in reduced time
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 M-CENK cells with higher CD16 expression and enhanced cytotoxicity against tumor cells, enabling effective ADCC and potentially treating various cancers, including solid tumors and leukemias, with a faster production timeline.
Implementation Method 1
removing CD3+ cells and CD14+ cells from the blood sample to obtain a CD3− CD14− population of cells is by magnetic cell separation
Implementation Method 2
incubating the CD3− CD14− population of cells with a first cytokine composition comprising a stabilized IL-15 analog or fusion protein comprised thereof for a first period, and incubating the CD3− CD14− population of cells with a second cytokine composition comprising i) IL-15 or a stabilized derivative thereof, ii) IL-18 or a stabilized derivative thereof, and iii) IL-12 or a stabilized derivative thereof
Data Source
AI summary
Provided herein are compositions and methods related to potent cytotoxic M-CENK cells from CD3/CD14 depleted apheresis products.