CISH-Knockout NK Cells for Low-Dose Cytokine Therapy

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Solution Overview

Problem

Existing NK cell therapies for cancer and infections face challenges due to NK cell exhaustion and the need for high doses of cytokines like IL-2 and IL-15, which cause systemic toxicity.

Innovation Solution

CISH−/− modified NK cells, derived from human induced pluripotent stem cells, exhibit hypersensitivity to low concentrations of IL-2 and IL-15, maintaining expansion and anti-tumor functions without the need for high cytokine doses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high doses of cytokines (IL-2 and IL-15) are used to maintain NK cell expansion and function, then NK cell activity and anti-tumor function are improved, but systemic toxicity increases

Engineering Contradiction:

ImproveNK cell activityVSAvoidsystemic toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the CISH gene expression status in NK cells (changing from wild-type to knockout), which fundamentally alters the cytokine signaling parameters. This genetic modification creates NK cells that respond more sensitively to cytokines, allowing effective function at lower doses and reducing toxicity while maintaining anti-tumor activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a modified version of NK cells by copying the successful wild-type NK cell phenotype but with the CISH gene deleted. This generates a new cell line (CISH−/− NK cells) that inherits the beneficial properties of wild-type NK cells while lacking the harmful CISH inhibitor, enabling them to function effectively with reduced cytokine doses

Inventive Principle:

Principle #26Copying

2Quantity of substance

If CISH gene is deleted to increase NK cell sensitivity to IL-15, then NK cell expansion and function are improved with lower cytokine doses, but the complexity of cell modification increases

Engineering Contradiction:

Improvecytokine doseVSAvoidcell modification complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent extracts and removes the CISH gene from the NK cell genome using CRISPR-Cas9 technology. By taking out this specific inhibitory gene, the NK cells lose the negative regulation on IL-15 signaling, resulting in heightened sensitivity and expanded function without requiring complex multi-gene modifications or additional therapeutic agents

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS20250255933A1Modification of Immune Cells to Increase Activity

Publication Date: 2025.08.14 RGT UNIV OF CALIFORNIA

AI summary

Compositions, methods of making, and using modified immune cells such as NK cells to treat cancer, viral and microbial infection. The modified CISH−/− NK cells exhibit hypersensitivity to cytokines such as IL-2 and/or IL-15 and maintain expansion and anti-tumor functions.