Gene-Edited Immune Cells for Reduced AICD and Host Rejection

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Solution Overview

Problem

Poor persistence and susceptibility to host-versus-graft responses, activation-induced cell death (AICD), and graft-versus-host-disease (GvHD) limit the effectiveness of allogeneic CAR-T and CAR-NK cells in immunotherapy, while NK cell activation and recognition mechanisms pose additional challenges.

Innovation Solution

Genetic modification of immune cells to reduce or eliminate the expression and function of proteins such as SPPL3, FADD, FAS, CASP8, ARID1A, BAK1, BID, ETS1, IKZF2, and HIST1H1B, combined with engineered receptors like CARs, to enhance persistence and reduce AICD and HvG responses, using CRISPR/Cas9 and iBAR systems for targeted editing.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If allogeneic immune cells are used for therapy, then off-the-shelf products can be provided suitable for many patients, but the cells are rejected by the host immune system due to HLA recognition

Engineering Contradiction:

Improveadaptability to multiple patientsVSAvoidpersistence of immune cells

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent extracts and removes the problematic HLA class I molecules from the allogeneic immune cells by knocking out the B2M gene, which is essential for HLA class I expression. This extraction of the immunogenic component allows the cells to evade host immune recognition while maintaining their therapeutic function

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the harmful effect of HLA expression (immune rejection) into a benefit by using CRISPR/Cas9 to deliberately knock out B2M, thereby creating HLA class I-deficient cells that are resistant to host-versus-graft rejection. The harm of immune recognition is transformed into protection against rejection

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Reliability

If HLA class I expression is reduced to prevent host T cell recognition, then allogeneic T cell rejection is reduced, but the cells become targeted by host NK cells

Engineering Contradiction:

Improveresistance to T cell rejectionVSAvoidsusceptibility to NK cell killing

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces an intermediary mechanism by knocking out multiple genes (B2M, FAS, FADD, CASP8) that collectively mediate resistance to both T cell and NK cell attacks. This multi-gene knockout strategy creates a composite protective phenotype that balances evasion of HLA-restricted T cells while reducing susceptibility to NK cell recognition

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If immune cells are activated to perform therapeutic function, then they can kill tumor cells effectively, but they undergo activation-induced cell death

Engineering Contradiction:

Improvetumor cell killing efficiencyVSAvoidpersistence of immune cells

Core Design Contradiction:

ProductivityVSDuration of action of moving object

Solution Approach 1:

The patent converts the harmful effect of activation-induced cell death into a benefit by knocking out the Fas-FasL apoptosis pathway genes (FAS, FADD, CASP8). This allows the immune cells to remain activated and functional for extended periods without undergoing AICD, thereby maintaining both high productivity and long persistence

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent changes the biological parameters of the immune cells by modifying the expression levels of key apoptosis pathway components through gene knockout. This parameter change (reducing Fas pathway activity) shifts the cell fate from activation-induced death to sustained survival, enabling long-term persistence while maintaining activation state

Inventive Principle:

Principle #35Parameter changes

4Reliability

If multiple genes are knocked out to achieve comprehensive protection, then resistance to rejection and AICD is improved, but the complexity of genetic modification increases

Engineering Contradiction:

Improveresistance to rejection and AICDVSAvoidcomplexity of genetic modification

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex genetic modification process into multiple independent CRISPR/Cas9 targeting steps, each focusing on a specific gene (B2M, FAS, FADD, CASP8). This segmentation allows systematic optimization of each gene knockout while maintaining overall process manageability and enabling modular implementation

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20260048120A1Modified immune cells and uses thereof

Publication Date: 2026.02.19 PEKING UNIV

AI summary

It relates to immune cells (e.g., T cells such as CAR-T cells, NK cells such as CAR-NK cells) modified to have no or reduced expression and/or function of one or more target proteins selected from the group consisting of: Signal Peptide Peptidase Like 3 (SPPL3), FADD, FAS, CASP8, ARID1A, BAK1, BID, ETS1, IKZF2, and HIST1H1B (such as SPPL3), uses thereof, and methods for generating thereof. Also provided are uses of the one or more target proteins (e.g., SPPL3) as a biomarker.