Autologous NK Cell Reprogramming via Transcription Factor Combinations

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Solution Overview

Problem

Current methods for generating NK cells are complex, time-consuming, and limited in scalability, with allogenic iPSC-derived NK cells facing immune rejection and persistence issues, while primary NK cells are difficult to obtain in large numbers for cancer immunotherapy.

Innovation Solution

A novel method involving the use of a combination of transcription factors such as ETS1, TBET, NFIL3, and EOMES to directly reprogram cells into NK cells, enabling fast and reproducible generation of autologous NK cells with enhanced persistence for immunotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If allogenic iPSC-derived NK cells are used for immunotherapy, then NK cell availability is improved, but immune rejection and persistence issues occur

Engineering Contradiction:

ImproveNK cell availabilityVSAvoidimmune persistence

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

Instead of using allogenic NK cells from external donors, the invention inverts the approach by reprogramming the patient's own somatic cells into NK cells, creating autologous NK cells that are immune-compatible and can persist long-term in the patient's body without rejection

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If primary NK cells are obtained for immunotherapy, then NK cell functionality is improved, but scalability and manufacturing efficiency deteriorate

Engineering Contradiction:

ImproveNK cell functionalityVSAvoidmanufacturing scalability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention segments the complex process of NK cell generation into distinct stages: (1) introduction of transcription factors into somatic cells, (2) reprogramming into intermediate states, and (3) differentiation into mature NK cells. This segmented approach enables scalable manufacturing while maintaining functionality

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention performs preliminary action by pre-introducing transcription factors (ETV6, GATA2, TAL1, etc.) into somatic cells before differentiation, preparing the cells in advance for efficient NK cell conversion and enabling scalable production

Inventive Principle:

Principle #10Preliminary action

3Reliability

If complex differentiation protocols are used to generate NK cells, then NK cell quality is improved, but manufacturing time and complexity increase

Engineering Contradiction:

ImproveNK cell qualityVSAvoidmanufacturing time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The invention extracts and utilizes the core reprogramming machinery (transcription factors) from complex differentiation protocols, simplifying the process by focusing on the essential genetic elements that drive NK cell conversion while maintaining quality

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes key parameters of the differentiation process by using specific transcription factor combinations and optimized culture conditions (cytokines, growth factors) to accelerate NK cell generation while maintaining quality standards

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20240018200A1Compositions, constructs and vectors for cell reprogramming

Publication Date: 2024.01.18 ASGARD THERAPEUTICS AB

AI summary

The present disclosure relates to compositions, vectors, constructs, cells and methods for the reprogramming of cells into natural killer (NK) cells or progenitors. In particular, it relates to a combination of transcription factors for the reprogramming of cells.